Pathogenesis of Neuropathic Pain: Diagnosis and Treatment 3030914542, 9783030914547

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Pathogenesis of Neuropathic Pain Diagnosis and Treatment Daryl I. Smith Hai Tran Editors Illustrations by Glen Hintz

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Pathogenesis of Neuropathic Pain

Daryl I. Smith  •  Hai Tran Editors

Pathogenesis of Neuropathic Pain Diagnosis and Treatment Illustrations by Glen Hintz, MS

Editors Daryl I. Smith School of Medicine University of Rochester Rochester, NY, USA

Hai Tran School of Medicine University of Rochester Rochester, NY, USA

ISBN 978-3-030-91454-7    ISBN 978-3-030-91455-4 (eBook) https://doi.org/10.1007/978-3-030-91455-4 © Springer Nature Switzerland AG 2022 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

This book is dedicated to my parents, Mrs. Josephine Loretta Smith, and Professor William Reeves Smith (1926–2018). Without their love, endless support, and inspirations, this work would never have been possible. Daryl I. Smith, MD I dedicate this work to my cherished family for their love, understanding, and unwavering support; to my friends for their advice and friendships; and to my mentors, teachers, and the individuals that I have encountered and will meet, for who I am today is the result of what I have learned from them. Hai Tran, MD

Preface

One of the most significant challenges clinicians face is the diagnosis and management of neuropathic pain. Neuropathic pain has diverse pathogenetic origins. As clinicians, we are often limited to either pharmacologic treatment regimens or procedural interventions which center upon neural blockade. This oversimplified set of constructs for dealing with neuropathic pain is driven in part by a lack of detailed sources which adequately discuss either theoretical or proven bases of each of the pathogenetic origins of neuropathic pain. This book will create a comprehensive source on the pathogenic origins of neuropathic pain. It will cover in detail the molecular bases of some currently known neuropathies by their pathogenetic origins. Clinicians will be able to consult an up-­ to-­date resource on this topic so they can tailor more specific and more effective treatment regimens for their patients. For basic researchers, this book is a general resource to better direct research on neuropathy-specific molecular mechanisms. The improved understanding of the pathogenesis of neuropathic pain can then be used to develop more specific and more effective manipulations of these pathways. This book is a resource on a syndrome that demands improved understanding by clinicians and researchers alike so that treatment options for patients are not categorically limited to a pill or a needle. If we understand the origins of our patients' neuropathic pain, we can work cooperatively toward ameliorating it with tailored therapies that don't create societal diseconomies and that ultimately are effective in helping patients. The need for this book will hopefully seem obvious to those practitioners who regularly combat neuropathic pain. The noted twentieth-century psychologist, Abraham Maslow, is quoted as saying, “to the man who only has a hammer, everything he encounters begins to look like a nail [1]”. I would proffer that a similar adage might be, “when faced with neuropathic pain everything warrants a gabapentanoid.” Drug binding at the α2-δ subunit of the voltage gated calcium channel in the pre-synaptic membrane is in many cases of significant analgesic value. Unfortunately, a high number of mechanistically unique neuropathic pain syndromes do not respond to this intervention. What is needed then are equally effective and more specific treatments. In this light, this book attempts to accomplish an examination of neuropathic pain from the inside out. In other words, we emphasize the fact that neuropathic pain is actually the end result of a final common pathway. A pathway that is reached by several, different, very specific molecular and cellular routes. The vii

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variability in these routes complicates our ability to treat. For instance, at least 12 different origins of neuropathic pain exist. These include well-known variants such as diabetic peripheral neuropathy, post-mastectomy pain syndrome, post-stroke neuropathy; chemotherapy-induced peripheral neuropathy, and migraine, to name a few. Yet each evolves via very different molecular interactions which ultimately result in potentially debilitating symptoms. Gabapentinoids, opiate analgesics, non-­ steroidal anti-inflammatory drugs, local anesthetics, and other adjuncts may be used in sequence or in combination, but the results are less than reliable. Understanding the earlier steps in the cascade and a knowledge of potential manipulations of those steps which are unique to specific etiologic variants are essential to creating effective intervention separate and apart from the usual therapeutic “hammers” that are currently employed. This book should serve first as a summary collection of the neuropathies encountered in clinical practice. In conjunction with this summary, it should also describe in some detail the molecular basis of these specific neuropathies. These descriptions are intended to make it apparent to both clinicians and basic researchers that work is necessary in both the laboratory and at the bedside to develop interventions to target those mechanisms that have yet to be brought to the bench. In Section 2 of this textbook, we emphasize peripheral mechanisms of nerve fiber sensitization. This comprises the proverbial nuts and bolts of neuropathic pain and is responsible for the recognized individuality of certain syndromes. Thus, the emphasis of this section is upon specific receptors involved in the various sensitization cascades, the ion channels that contribute to the differences in sensitization patterns, and, finally, the kinases and neutrophins that are essential to pain pathways and to the characterization of neuropathic pain while also serving as potential markers for the presence and intensity of neuropathic pain. This comprises both the proverbial as well as the literal nuts and bolts of neuropathic pain and is responsible for the recognized individuality of certain syndromes. The next section, Section 3, examines the first in the discussion of disease-related neuropathies: diabetic neuropathy. By theoretical etiologic standards, diabetic neuropathy is not a single entity. A number of pathways have been postulated to be the critical factor in the development of this malady, these include galactose neuropathy, the glycochelates and transitional metals pathway, axon reflex vasodilatation, and diabetes-related protein kinase neuropathy. The classic complex regional pain syndrome (CRPS) is discussed here with emphasis on the differences between the two recognized subtypes (1 and 2). Here, we attempt to review the literature that explains fundamental differences between the subtypes in an effort to establish new therapeutic beachheads. These may rationale for significantly different pharmacologic management of the subtypes. A study of alcohol-related neuropathy follows, with special attention to its existence as a sympathetically mediated entity as evidenced by the associated cardiac autonomic neuropathy that frequently occurs with the peripheral neuropathic component. A logical sequel to this discussion is the next chapter which is a discussion of perfusion-related neuropathies. Again, the role of the sympathetic nervous system is iterated, but here we study the entity in light of direct, dynamic changes in the

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neurovasculature. Hypertension- and hypotension-related neuropathies are discussed in addition to the more obscure neuropathies such as ischemic monomelic neuropathy and Cuban endemic neuropathy. Following this discussion, we return to the disease-based neuropathy category with a discourse on uremic neuropathy and the roles of molecular products of impaired renal function. These include creatine, guanidine, uric acid, and oxalic acid. The syndrome also includes crossover molecules that both mediate neuropathic pain and serve as putative markers for its presence and the intensity of neuropathic pain, e.g., tumor necrosis factor alpha (TNF-α) as well as interleukin-6 (IL-6). The molecular players in the section on uremic neuropathy serve as a transition point to the discussion of exogenous chemical causes of neuropathic pain. In the three chapters that follow, we discuss chemotherapy-induced peripheral neuropathy (CIPN) with considerations of antimicrotubule agents, proteasome inhibitors and anti-retroviral chemotherapeutic agents, and antibiotic- and antifungal-related neuropathies. Finally, infectious agents known or suspected to cause neuropathic pain and environmental toxins linked to this syndrome will be considered. Certain neuropathic syndromes such as post-thoracotomy pain syndrome and post-mastectomy pain syndrome are not discussed in this textbook. This is not because they are outside the scope of this book but, to the contrary, they so closely fit the mechanistic pathways discussed in the chronification section of this textbook. The summary section will attempt to find commonality among these etiologies in an effort to tie the unique characteristics of the diverse originators of neuropathic pain together. Neuropathic pain will be studied from the inside out as well as from the outside in.

Reference 1.  Maslow A. The psychology of science: a reconnaisance. Vol. 1. Harper Collins; 1966. p. 168. Rochester, NY, USA Rochester, NY, USA

Daryl I. Smith Hai Tran

Acknowledgments

We would like to thank Peter J “PJ” Papadakos, MD, for his invaluable mentorship in the creation of this work. We would like to thank Mr. Glen Hintz, MS, for the superb illustrations. We would also like to thank Ms. Teresa Rios for her patient and energetic administrative support and Ms. Linda Hasman for her expert research assistance.

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Contents

Part I Mechanisms of Chronification of Acute Pain  Nerve Growth Factor and Neuropathic Pain��������������������������������������������������   3 Alfred Malomo Jr and Daryl I. Smith  Protein Kinase C and the Chronification of Acute Pain��������������������������������  27 Benjamin Hyers, Donald S. Fleming, and Daryl I. Smith  Tumor Necrosis Factor-Alpha and the Chronification of Acute Pain ����������  55 Daryl I. Smith and Hai Tran  Tetrodotoxin and Neuropathic Pain ����������������������������������������������������������������  85 Jimmy Liu and Daryl I. Smith  Epigenetic Alterations in the Nervous System in Neuropathic Pain ������������  93 Daryl I. Smith Part II Neuropathic Syndromes  Pathogenesis of Neuropathic Pain: Diagnosis and Treatment ���������������������� 105 May Wathiq Al-Khudhairy, Abdullah Bakr Abolkhair, and Ahmed Osama El-Kabbani  Chemotherapeutics That Impair Microtubule Function: Axonopathy and Peripheral Neuropathies������������������������������������������������������������������������������������ 125 Hai Tran and Gail V. W. Johnson Diabetic Peripheral Neuropathy���������������������������������������������������������������������� 143 Hai Tran and Daryl I. Smith Alcoholic Neuropathy���������������������������������������������������������������������������������������� 155 Adaora Chima and Daryl I. Smith Uremic Neuropathy�������������������������������������������������������������������������������������������� 189 Anil Arekapudi and Daryl I. Smith Perfussion-Related Neuropathies �������������������������������������������������������������������� 213 Amie Hoefnagel, Oscar Alam-Mendez, and Michael Ibrahim

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Pressure-Induced Neuropathy and Treatments���������������������������������������������� 225 Daryl I. Smith, Syed Reefat Aziz, Stacey Umeozulu, and Hai Tran Infectious Neuropathies������������������������������������������������������������������������������������ 249 Hai Tran, Daryl I. Smith, and Eric Chen Index�������������������������������������������������������������������������������������������������������������������� 281

Contributors

Abdullah  Bakr  Abolkhair, MBBS  Department of Anesthesia, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia May  Wathiq  Al-Khudhairy, BDS, DMSc  Oral Diagnosis and Maxillodacial Surgery Department, Riyadh Elm University, Riyadh, Saudi Arabia Oscar  Alam-Mendez, Jackson, MS, USA

MD  University

of

Mississippi

Medical

Center,

Anil  Arekapudi, MBBS, MD, DABA, FRCPC  Oakville Trafalgar Hospital, Oakville, ON, Canada Department of Anesthesia, McMaster University, Hamilton, ON, Canada Syed  Reefat  Aziz, BS  University of Rochester Medical Center, Department of Anesthesiology, Rochester, NY, USA Eric  Chen, MD  Department of Anesthesiology & Perioperative Medicine, University of Rochester Medical Center, Rochester, NY, USA Adaora Chima, MBBS, MPH  Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Ahmed  Osama  El-Kabbani, MBBS  Department of Anesthesiology, Matareya Teaching Hospital, Cairo, Egypt Donald S. Fleming, BS  University of Rochester School of Medicine and Dentistry, Medical Humanities, Department of Anesthesiology and Periopoerative Medicine, Rochester, NY, USA Amie  Hoefnagel, MD  Department of Anesthesiology, University of Florida College of Medicine, Jacksonville, FL, USA Benjamin Hyers, MD  Icahn School of Medicine at Mount Sinai, Department of Anesthesiology, Perioperative, and Pain Medicine, New York, NY, USA Michael  Ibrahim, MD  University Jacksonville, FL, USA

of

Florida

College

of

Medicine,

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Contributors

Gail V. W. Johnson, PhD  Department of Anesthesiology, University of Rochester, Rochester, NY, USA Jimmy Liu, MD  University of Rochester, Rochester, NY, USA Alfred  Malomo Jr, MA  The State University of New  York at Binghamton (Binghamton University), Binghamton, NY, USA University of Rochester School of Medicine and Dentistry, Department of Anesthesiology and Perioperative Medicine, Rochester, NY, USA Daryl I. Smith, MD  University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA Hai Tran, MD  URMC Strong Memorial Hospital, Department of Anesthesiology and Perioperative Medicine, Rochester, NY, USA Stacey Umeozulu, BS  Xavier University of Louisiana, New Orleans, LA, USA

About the Editors

Daryl I. Smith, MD  is Associate Professor of Anesthesiology and Perioperative Medicine at the University of Rochester in Rochester, New  York, where he is a former chief of the acute pain service. He is a graduate of the Brown University Program-in-Medicine, Providence, R.I. He completed his residency and pain fellowship at the University of Chicago Medical Center, Chicago, IL.  His research interests emphasize the treatment of neuropathic pain syndromes and the development of delivery systems for neural blockade procedures. Hai Tran, MD  is a pediatric anesthesiologist. He graduated from SUNY Upstate Medical University. He completed his residency in New York City and pediatric anesthesia fellowship in Texas. His clinical interests are regional anesthesia and anesthetic management of patients with complex developmental malformations. His research focuses on regional anesthesia education and the prevention and alleviation of acute and chronic pain.

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Part I Mechanisms of Chronification of Acute Pain

Nerve Growth Factor and Neuropathic Pain Alfred Malomo Jr and Daryl I. Smith

Introduction Neurotrophins are a family of neuronal growth factors. They are overexpressed in a number of disease states and include nerve growth factor (NGF); brain-derived neurotrophic factor (BDNF); and neurotrophin-3 (NT-3) and neurotrophin-4 or 5 (NT-4/5). They bind with varying degrees of specificity to NT receptors, TrkA, TrkB and p75NTR; and NT receptor-interacting proteins, MAGE and NDN [1]. NGF is considered the founding member of the neurotrophins family of proteins. It was discovered over 60 years ago when Levi-Montalcini investigated a method to quantify the stimulating effect of a tumor on neural cells [2] and found that the tumor released a substance that promoted neurite outgrowth as well as nerve cell differentiation. NGF is a 26 kDa dimeric protein that is composed of two13 kDa monomers. It is synthesized as a proneuroptrophin (proNGF) that is cleaved into its final form by endoproteases in proximity of the trans Golgi network. The 13 kDa monomers contain a cysteine knot motif which is comprised of three disulfide bridges [Image of disulfide bridge]. The III-VI; II-V; and the I-IV cysteine residues are bound; and the I-IV bond (penetrating disulfide bond) traverses three β strands. The external surface of NGF is composed of loop regions which, because of their charges and polarity, are responsible for NGF solubility and its ability to function as a signaling A. Malomo Jr The State University of New York at Binghamton (Binghamton University), Binghamton, NY, USA University of Rochester School of Medicine and Dentistry, Department of Anesthesiology and Perioperative Medicine, Rochester, NY, USA D. I. Smith (*) University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_1

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protein. NGF binds two distinct receptors: p75NTR and TrkA receptors with differing degrees of affinity and specificity. While the p75NTR receptor displays pan-­ neurotrophin binding properties, it binds NGF with low nanomolar affinity. Its binding with NGF can induce either proapoptotic or prosurvival signaling; and p75NTR has also been shown to upregulate the expression of Trk receptors as well the affinity of the TrkA receptor for NGF. The TrkA exhibits much greater receptor affinity for NGF demonstrating picomolar affinity in the midst of other neurotrophins. When NGF binds TrkA the NGF dimerizes and autophosphorylation occurs between the intracellular kinase domains of each monomer. Among the consequences of activation downstream signaling activation is the recruitment of phospholipase and the subsequent effects upon protein kinases [3]. Generally, while the abnormally high levels of NGF are thought to contribute to the pain and hyperalgesia symptoms [4] in syndromes such as headache, cystic pancreatitis, arthritis, and cystitis; elevations of NGF in diabetic peripheral neuropathy are argued to be a result of NGF dysregulation and reflect NGF insufficiency in the physiologic attempt to correct and repair hyperglycemic-mediated neuronal damage. The expression of NGF after an acute insult and subsequent hyperexcitability both peripherally and centrally (at least in the DRG) is a common pathway that we may be observing in the disease conditions discussed in this chapter. However, we must resist any tendencies to limit our consideration to this pathway alone. For example, in murine models, intrathecal injection of NGF ameliorates DPN pain-related behavior. Despite the seeming aberrancy in the setting of DPN, antagonism of NGF and its signaling is seen as a promising therapeutic strategy. It is important to note that NGF is not synthesized into its final form, rather a proneuroptrophin or immature molecule is first synthesized which is then cleaved by trans Golgi network endoproteases to form the mature NGF [5]. The solubility characteristics of NGF make it available to function as a signaling protein. This is the result of charged residues in the several loop regions on the external surface of the NGF molecule. This signaling activity is mediated via binding at the p75NTR and TrkA receptor. These receptors are distinct with the TrkA receptor exhibiting high binding (picomolar) affinity and selectivity for NGF in the presence of other neurotrophins [6, 7]. The p75NTR receptor, on the other hand, behaves as a pan-neurotrophin receptor and has been shown to bind NGF and other neurotrophins with low (nanomolar) affinity. The p75NTR receptor has the ability to augment the expression of TrkA and its affinity for NGF [8]. The physiologic consequences of NGF binding at the p75NTR receptor are diverse in that either apoptosis or cell survival pathways can be activated by NGF binding. Following binding of NGF at the TrkA receptor, the neurotrophin dimerizes and autophosphorylation between the intracellular kinase domain of each monomer results in a signaling cascade which causes activation of the Ras-mitogen activated protein pathway (MAPK-pathway); the phosphatidylinositol-3 kinase (PI3K) pathway and the recruitment of phospholipase [3, 9]. While the binding of NGF to TrkA is thought to be responsible for neuronal survival and neuronal differentiation, [10] dysregulation of NGF is known to be a contributing factor of neuropathic pain, with NGF signaling increase causing both augmented neurite

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outgrowth and nociceptor sensitivity [11]. In both human and non-human models, chronic pain exhibits abnormally high levels of NGF [4, 11].  Painful syndromes known to be associated with increased NGF levels and NGF-dependent signaling include diabetic neuropathy, arthritis, cystitis, pancreatitis and headache. It follows that antagonism of NGF and its receptor binding are logical targets for therapeutic strategy. Given the number of molecular steps involved in the plethora of post-NGF-­ TrkA binding events, it would be unwise to limit our scientific imaginations to these two components as targets of treatment. This limitation would drastically hinder the potential for uncovering more specific targeted therapies. It should be noted that in its immature or ‘pro” form, NGF (proNGF) is a potent apoptotic agent that functions to regulate aberrant neuronal growth and synapse formation during development [12]. NGF plays critical roles in a plethora of other physiologic processes including the mediation of inflammation; the development of  neuropathy; CNS mediated analgesia in diabetic neuropathy; [13, 14] the development and maintenance of sensory neurons; the promotion of sensory and sympathetic neuronal survival; and the mediation of chronic pain. NGF and its interaction with its highly specific receptor tropomyosin receptor kinase A (trkA) have been well characterized. Molecular as well as genetic interventions have been developed which target this pathway. These present promising methods in the treatment of a variety of nociceptive and neuropathic pain conditions [15]. This chapter focuses upon each of these roles and attempts to combine them into a reinforcement of a school of thought which emphasizes creative therapeutic approaches to NGF-mediated neuropathic pain.

Mechanism of Chronification The mechanism of chronification of acute pain with respect to NGF is a fascinating subject which we will cover in as much depth as is reasonable in a textbook of this nature. We will begin with an overview, examine specific, currently pertinent details and molecular interactions, then examine extant as well as current clinical interventions that may prove valuable in future work. The specific role of NGF in the chronification of acute pain is via gene expression responses. One important point of focus is the specific manipulation of these genetic routes.  This pathway involves activation of mitogen activated protein kinases which can transduce pathological signals in the injury or disease state, and developmental signals in the normal state. This activation is not exclusive to NGF since pro-­nociceptive cytokines and other neurotrophic factors can activate MAPKs. The key step in this activation is the induction of hyperexcitability of DRG sensory neurons [16, 17] with subsequent augmentation of current density of tetrodotoxin-R sodium currents in these neurons [18, 19]. Direct phosphorylation of the Nav 1.8 TTX-R channel is essential for the activation of the p38 MAPK-mediated increase in current density.

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Prevention of direct phosphorylation at the two phosphoacceptor serine sites at the L1 portion of the channel can abolish the pp38 effect (increased excitability) on Nav 1.8. Subsequent studies have taken closer looks at the role of NGF in hypersensitization as the critical step in the chronification of acute pain via genetic changes in sodium channels and TrkA receptor expression [3, 20]. The role of NGF in the development of chronic pain is clearly multifactorial. For instance, release of the well-known neurotransmitter substance P (SP) is affected by NGF. NGF increases the expression and content of substance P in developing and mature spinal sensory neurons in an in vitro murine model. Skoff et al.  demonstrated that there is a low but detectable basal rate of substance P release in cultured, mature rat sensory neurons grown without NGF, and that this release of SP increases with depolarization by KCl. When the group added NGF to the culture, KCl –based depolarization tripled the amount of SP released. Glial cell-derived neurotrophic factor (GDNF) addition to the naïve media also resulted in a SP release that was very similar to that of NGF. The authors speculated that NGF increased SP release indirectly by increasing intracellular stores [21]. We consider, here, the importance of SP to the development of chronic pain in light of its relation to NGF. Substance P is a highly conserved member of the tachykinin peptide family. A minority of neurons in certain brain areas express neurokinin receptors (NKRs); [22] and SP itself is produced by both microglia and immune cells [23]. It is the repetitive, low-frequency firing of sensory afferent nerves during inflammation and trauma that enhances pain sensitivity by altering synaptic efficacy and initiating excitation-transcription coupling in spinal neuronal nociceptors. The elaboration of post-synaptic dendritic structures de novo plays an important role in the neuroplastic changes that cause establishment of chronic pain pathways. These changes increase synaptic strength and neuronal excitability that results in long term potentiation (LTP). Substance P enhances the generation of LTP via its increased extracellular concentration which results from the NGFmediated genetic alterations that augment the intracellular expression of SP. Following injury, the increase in neuronal sensitivity and the progression to neuropathic pain may not be initiated, necessarily, by an increase in NGF. Indeed, there may be another  initiating event. Goettl et  al. in 2004 observed that in peripheral neuropathy, dorsal column fibers that synapse in the nucleus gracilis mediate expression of mechanical allodynia and display hyperexpression of BDNF in a murine model. They turned their attention to measurements of mRNA expression of BDNF, NGF, and the neurotrophin receptors, TrkA, TrkB, and p75 one-week following ligation of spinal nerves L5 and L6. Of the mRNA expression measured, only p75 mRNA increased in the ipsilateral ligated spinal nerve. All other mRNA levels TrkA, TrkB and NGF decreased; and BDNF mRNA was undetectable. They concluded that the p75 receptor must therefore influence Trk activity and cell survival [24]. If this is the case then perhaps focus upon p75 manipulation as a therapeutic target is warranted since post-injury changes in p75 may be actually responsible for downstream NGF effects. The NGF-TrkA binding event has far-reaching consequences and several neurotransmitters, receptors, and ion channels are modulated and up-regulated by the

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NG

NGF

F

F NG

NGF

kA Tr

Ab

Trk A

A

T rk A

F

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G

T

N NGF

GF

N Trk A

NG F

GF

T A rk

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PGE H+ Bradykinin 5–HT ATP Histamine Inflammatory cell

Fig. 1  Schematic of release, receptor binding, and downstream effects of nerve growth factor (NGF). Cell types (purple) include eosinophils, lymphocytes, macrophages, mast cells and Schwann cells. High affinity NGF receptors (TrkA) binding can initiate a number of cascades which can result in modulation of potassium (red), sodium (yellow), calcium (blue); or upregulation of TRPV1 (orange) and ASIC3 (green) channels

event. As depicted in Fig. 1, these include ligand-gated ion channels (LGIC). The iconic channel representing this group is the transient receptor potential vanilloid type one or TRPV1. Activators of this receptor are heat and capsaicin. Other LGICs include the purinergic receptor, P2X, which binds ATP; and acid-sensing ion channels (ASIC) [25, 26]. NGF also acts indirectly upon non-neuronal cellular elements such as mast cells (See Fig. 1) which also express TrkA receptors and are stimulated by NGF to proliferate, degranulate and express IL10, serotonin and TNFα [27]. As a particularly fascinating downstream event of the NGF-TrkA binding there is increasing evidence that a number of pro-inflammatory cytokines and chemokines can sensitize nociceptors via direct binding at nerve terminals as well in injury spared neurons [26]. TNFα for instance can induce those sensory neurons to further express receptor components capable of transducing extracellular TNFα; [28] IL1 and IL6 [29] thus feeding the sensitization cascade. In a three-step interaction, Kagan et al. in a 1992 work described the insertion of TNFα into a cell membrane where it formed its own ion channel as part of the inflammatory response to neural injury (Fig. 2). The insertion was observed into the

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A. Malomo Jr and D. I. Smith Tumor Necrosis Factor TNF

Tryptophan

© G. Hint z 2020 +

Na pH 8

pH 4

Fig. 2  Insertion of TNFα into a cell membrane forming an ion channel as part of the inflammatory response to neural injury. TNFα inserts into the hydrocarbon core of the phospholipid bilayer. The insertion event is related to pH

hydrocarbon core of the phospholipid bilayer and was inversely related to pH, i.e., the insertion rated increased with decreasing pH.  TNFα has also been shown to induce oligodendrocyte necrosis, myelin dilatation, and periaxonal swelling which opens Na+ channels. Further studies showed that the addition of TNFα to human histiocytic lymphoma cell culture preparation increased sodium uptake by 100–300% in the presence or absence of the Na/K-ATPase (Na-K+ pump) inhibitor oubain. This reinforced the de novo creation of Na+ channel theory [30]. Interestingly activated macrophages and osteoclasts generate an acidic micro environment [31]. This supports the pH-dependent insertion of the expressed TNFα into the target tissue thus completing another step towards sensitization. Genetically determined pain insensitivity syndromes may give guidance to the understanding and subsequent treatment of neuropathic pain syndromes. A clinical episode described by Einarsdottir et al. reinforces the clinical importance of the role of NGF in pain development. This group described the mapping and identification of the gene responsible for loss of deep pain perception in a Scandinavian family. These individuals also displayed an impairment in the sensation of temperature, but they maintained normal mental abilities and most other neurologic responses. The group identified the 8.3 Mb region on chromosome 1pll, 2-pb3.2 as the common locus for the characteristic mutation location corresponding to the coding region of the nerve growth factor beta gene which was specific to the disease haplotype. The mutation appears to separate the effects of NGF involved in the development of

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CNS functions such as learning and processing information from those involved in peripheral pain pathways [32]. Congenital insensitivity to pain with anhydrosis (CIPA) is another syndrome with some phenotypic similarities to the case report discussed above. It is an autosomal recessive disorder, which results from a mutation of the NTRK1 gene mutation. Over 105 NTRK1 mutations have been described, however clinical evidence thus far has correlated four distinct NTRK1 mutations with varying degrees of clinical severity [33]. The disease is characterized by loss of deep pain perception, which is attributed to the absence of nociceptive sensory innervation, and a result of the loss of NGF-TrkA-dependent and NGF-p 75 NTR  – dependent sensory neuron development and survival. The syndromes are currently known by the names hereditary sensory and autonomic neuropathy type V (HSANV) and a more recently reported HSAN IV.  Both syndromes are comprised of lack of pain appreciation. Patients suffering from the HSAN IV variant demonstrate anhydrosis and mild to moderate mental retardation [33–35].

Clinical Considerations A number of painful syndromes of diffuse presentations and system physiology include NGF as either an algesic substance, a pain marker or both. NGF has been implicated in the development of neuronal hypersensitivity, hyperalgesia and neuropathic pain. In the setting of diabetic peripheral neuropathy in murine models it has been shown that there are expression deficits in NGF and  in the trkA receptor. Tomlinson et al. also showed that this expression deficit resulted in decreased retrograde axonal transport of NGFD and decreased support of NGF-dependent sensory neurons; [36, 37] and the neuropathic changes in small nerve fibers are ameliorated by administration of exogenous NGF [38].

Diabetic Neuropathic Pain The restorative role of NGF in painful diabetic neuropathy may be the result of induction of mu-opiate receptor gene expression. In a 2014 study, Shagura et al. examined streptozotocin induced diabetes mellitus in a murine model and focused upon the ability of NGF treatment to restore μ-receptor expression and GPCR binding. They hypothesized that replenishment of μ-receptor density would allow binding of exogenous opioids, in particular fentanyl, and thus reverse the narcotic resistance noted in painful diabetic neuropathy. The group showed both the reduction in μ-receptor expression, and G-protein coupling in parallel with the loss of behavioral opioid responsiveness and the subsequent re-establishment of opioid responsiveness following intrathecally administered NGF [13].

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NGF expression has been shown to increase following certain therapeutic interventions for diabetic neuropathy. Low-level laser (LLL) therapy has analgesic, anti-­ inflammatory and beneficial biomodulating effects on mice with streptozotocin-induced DPN.  In particular, mechanical hypersensitivity improved after 7, 14, and 21 LLL therapy sessions, and NGF quantification assays showed a statistically significant increase in the neurotrophin [39]. An inverse relationship between NGF and TrkA positive nerve fibers was found in the footpad skin of streptozotocin-induced diabetic mice. This is consistent with previous data regarding overall neural morphology in this murine model with concomitant decrease in analgesic responsiveness [13] and neural repair capabilities (Evans, 2010). In the study, examining TrkA-positive intra-epidermal innervation there was a significant decrease in these fibers in the foot pad of diabetic rats [13]. The nerve injury subsequent to diabetes without the repair function benefits of  NGF and its potential role in the development of neuropathic pain is iterated here [40]. A study was conducted to examine the relationship of NGF in the dorsal root ganglion and the dorsal horn; and to examine the effects of exogenous mouse NGF upon expression of NGF in the dorsal horn, DRG and the mechanical pain threshold in streptozotocin-induced diabetic rats (Table 1) [41]. Of note is the fact that hyperalgesia occurred when NGF expression in the DRG decreased; and reduction of NGF in the dorsal horn was related to concomitant allodynia. The authors noted a significant elevation in the pain threshold 2 weeks after exogenous NGF administration which iterated the therapeutic value of NGF in diabetic neuropathy. They were unable to establish a relationship between dorsal horn and dorsal root ganglia expression of NGF. In a unique approach to treating streptozotocin-induced diabetes in a murine model the manipulation of endogenous NGF was examined. A Bioactive constituent from the rhizome of Dioscorea japonica Thunberg and Dioscorea nipponica Makino named DA-9801 was shown to increase endogenous nerve growth factor levels in streptozotocin-induced murine models of diabetic neuropathy. The therapeutic effect was demonstrated through the examination of thermal and mechanical hyperalgesia nociceptive test of limb withdrawal latency times. DA-9801 increased latency times in both tests. This suggests, again, that NGF may improve the damage produced via diabetic neuropathy. In addition, improvement in nerve conduction velocity as well as histologic recovery from nerve degeneration was shown. This suggests, again, that

Table 1  Brief summary of effects of exogenous NGF on the streptozotocin-induced diabetic murine model Event Mechanical pain threshold NGF expression (DH) NGF expression (DRG) (DH dorsal horn, DRG dorsal root ganglion)

Streptozotocin Induction (2wks)/duration ↓ / (8wks) ↓ / 4wks ↓ / 8wks

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NGF may improve the damage produced via diabetic neuropathy and that manipulation of NGF expression may be a viable therapeutic approach [42]. A 2011 study asserted the dysfunction of NGF production and/or utilization in the establishment of diabetic neuropathies. The group set thermal hyperalgesia, tissue alteration of NGF and sensory neuromodulators as primary and secondary outcomes in a murine model of streptozotocin induced diabetes. The animals were then treated with low-frequency electroacupuncture (EA) for 3 weeks. EA corrected the thermal hyperalgesia that followed streptozotocin induction. NGF and trkA increased in parallel in the spinal cords of these animals but this was reportedly counteracted by electroacupuncture. This study concluded that EA might have value as treatment of diabetic neuropathy but its findings cloud the previous assertion regarding the relationship of NGF and neuropathic pain in diabetic neuropathy [43].

Myofascial and Dermatologic Algesic syndrome produced by intramuscular injection of NGF is believed to be the result of a lasting sensitization of fascia nociceptors. This was tested by the injection of NGF into the lumbar erector spinae fascia of 14 healthy male volunteers. While no acute pain resulted in this study, NGF did induce a lasting, (ca. 14 days) fascia-­ level sensitization to mechanical and chemical stimuli. They concluded that fascia appears to be particularly prone to sensitization and that fascial nociceptors may contribute to acute or chronic muscle pain [44]. A second study performed in 2013 also looked at intramuscular injections of NGF in a human model and again NGF was shown to produce a progressive manifestation of soreness, mechanical hyperalgesia and temporal summation of pain as measured by computer-controlled pressure algometry. The study suggested that prolonged NGF exposure affects both peripheral and central mechanisms and may play a significant role in musculoskeletal pain conditions [45]. The role of skin in sensory transduction is vital and is influenced by neuronal and immunologic systems. Pain transmission via skin nociceptive receptors such as TRPV1 and Na voltage gated channels is well described however in 2010 mounting evidence suggested that keratinocytes expressed receptors that increased in number with the development of neuropathic conditions but that intra-epidermal nerve fibers did not. Pain processing at this level was the result of signaling pathways between Keratinocytes, nociceptors, and macrophages. Critical mediators included prostaglandins and NGF, which lead directly to nociceptor sensitization [46]. In another study, which focused upon the intraepidermal effect of NGF, human and porcine (human-like) models were employed to examine functional and sprouting neurite changes caused by intradermal injection of NGF. Intraepidermal nerve fiber (IENF) densities were assessed by immunohistochemistry in pigs and in human volunteers using the same NGF. Nerve conduction velocity was increased, and activity-dependent slowing of conduction velocity was reduced in both pigs and humans. Thus NGF was shown to cause both axonal and mechanical sensitization in the two models. There was no associated increase in IENF density [47].

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Musculoskeletal Disease The role of neurotrophins, especially NGF and BDNF, in human intervertebral disc disease was addressed in a 2014 work by Krock et al. [48] In this work they examined the inflammatory factors found in unregulated disc degeneration. They focused upon the that healthy and asymptomatic intervertebral discs tended to be aneural in comparison with degenerating, symptomatic intervertebral discs (IVD) which are often innervated. The exact mechanism by which degenerating discs in both disc cell cultures as well as in animal models are able to release increased levels of several nociceptive factors including NGF is unknown. Using cytokine arrays the group found that degenerating, symptomatic IVDs release more cytokines overall than healthy asymptomatic discs, and more nociceptive factors overall. When IELISA assays were employed the group found higher levels of NGF and BDNF in media in degenerating IVD cultures compared with healthy IVD.  Neurite sprouting which characteristically accompanied NGF was also measured and shown to increase. This correlated with the increase in NGF production in symptomatic IVD and was significantly reduced in the presence of anti-NGF antibodies [48, 49]. As of 2015, a total of 45 studies examining 15,664 patients had examined the role of α-nerve growth factors in chronic pain syndromes. The most frequently used antibody preparation was Tanezumab (26) followed by Fasinumab (9), and then Fulranumab (7). While most studies have focused upon osteoarthritis (21); low back pain therapy using α-NGF antibody has been examined (4 studies), in addition to a variety of other pain syndromes totaling 11 studies which include two diabetic neuropathic pain studies and three studies examining cancer pain. We performed a thorough review of the web site www.clinicaltrials.gov for the 10-year period between 2009–2019 to identify all registered active or completed clinical studies examining anti nerve growth factor antibody. Ten trials were identified. Six trials examined the following syndromes: low back pain, phantom limb pain, progressive supranuclear palsy, retinitis pigmentosa, multiple sclerosis, and unresectable metastatic melanoma. Which met the criteria of treating osteoarthritis-­ related pain alone. Only the studies involving osteoarthritis and low back pain utilized antibody administration for treatment of pain symptoms.

Urinary Tract Bladder pain, interstitial cystitis (IC), chronic pelvic pain syndrome (CPPS) chronic prostatitis (CP) and overactive bladder (OAB) all appear to be affected by NGF. In addition, there is some evidence to indicate that NGF may be a marker, which can be used as an indicator of the presence and/or the severity of these diseases. IC and bladder pain syndrome (BPS) constitute a chronic disease syndrome for which no reliable, effective treatment exists. The pain associated with disease is usually triggered by bladder filling and activation of mechanoreceptors likely mediated by the bladder afferents located in the trigone. Whether this can be classified as a pressure-induced neuropathy remains to be seen [50]. Pinto et al. targeted these

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afferents with trigonal injection using botulinum toxin A (BONTA) and subjective descriptions of post-injection pain, urodynamic data, and NGF and BDNF levels were determined. The authors reported that treatment was effective in 50% of the patients for 9 months. They also noted a correlation between symptomatic relief and a reduction in urinary NGF and BDNF [51]. Two subsequent studies examined the role of urinary proteins and serum cytokines in chronic prostatitis (CP); BPS/IC, CPPS, and OAB. In the first, Watanabe, et al. attempted to determine whether NGF levels in expressed prostatic secretions (EPS) correlated with symptom severity as determined by the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) questionnaire. NGF levels in patients with CP/CPPS correlated directly with pain severity, but there were no significant differences between NGF levels in EPS before and after treatment, i.e., treatment that did not result in at least a 25% decrease in total NIH-CPSI score from the baseline values. Successful treatment did, however, significantly decreased NGF level in EPS. The authors conclude that NGF might contribute to the pathophysiology of CP/CPPS and that NGF could be used as a new biomarker to evaluate the symptoms of CP/CPPS and the effects of treatment [52]. Both of these assertions are severely limited by the small sample size in this study however, and a larger population study needs to confirm these findings before practitioners can rely upon the results. The second study sought to  clarify the pathophysiology of OAB and IC/ BPS. Antimuscarinic agents are first-line therapeutic drugs in the treatment of these syndromes. When the diseases are refractory to antimuscarinics, CNS sensitization may be the mechanistic culprit. Kuo et al. examined this in a 2013 study in which they sought to exploit the heterogeneous nature of IC/BPS (ulcerative subtype versus nonulcerative subtype) by identifying non-invasive unique biomarkers of the variants and OAB. In both OAB and IC/BPS, increased levels of urine NGF and bladder tissue NGF have were identified. In addition, serum NGF and C-reactive protein (CRP) are elevated in both syndromes. Of note however is the fact that IC/ BPS but not OAB differ in that only IC/BPS involves an aberrant bladder urothelium cell differential pattern that results in the altered synthesis of proteoglycans, cell adhesion and tight junction proteins, and immunosurveillance molecules. The plethora of potential markers has led to examination of the urinary proteome as a whole as a source for individual biomarkers, or the urinary proteome and unique patterns within the proteome as a whole to differentiate between types of pathology [53]. The implication of NGF in the pathogenesis of CP/CPPS suggests that in addition to NGF function as a marker of pain severity that monoclonal antibodies against NGF may be of clinical value.

Cancer-Induced Bone Pain Nerve growth factor plays a major role in the chronification of acute pain by virtue of its ability to mediate the expression of neurotrophin receptors TrkA and p75 in nociceptive DRG neurons. While the exact time frame of this occurrence is the

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current subject of speculation, the acute nature of NGF in nociception is a bit surer. In 2005, Halvorson et  al. demonstrated in a murine model that when an NGF-­ sequestering antibody was administered to mice who had received an osteoclastogenic instillation of prostate cancer cells in a femur, that there was a significant reduction in both early and late stage bone cancer pain related behaviors. This reduction in bone cancer pain-related behavior was found to be greater than or equivalent to acute administration of clinically relevant doses of morphine sulfate. One observation from this study was that essentially all nociceptive innervation of the femur expressed trkA and p75 receptors [54]. Further studies on primary nociceptive innervation of bone by Castaneda-Corral et al. found relative quantitative differences of TrkA receptors that might explain the efficacy of anti-NGF and anti-TrkA antibody therapies in the treatment of cancer-­ related bone pain versus other types of acute pain. They found that 80% of unmyelinated or thinly myelinated sensory nerve fibers express TrkA in addition to calcitonin gene-related peptide (CGRP). The myelinated fiber that expressed TrkA co-expressed neurofilament 200 kDa (NF200). For our purposes as we search for markers of pain severity, we are served well by these finding. The group discovered that there was a density relationship of these molecules with respect to structural components of mature bone. They stated that the relative density of CGRP+, NF200 and TrkA+ − expressing nerve fibers per unit volume of skeletal tissue was periosteum > bone marrow > mineralized bone > cartilage with respective relative densities are 100:2:0.1:0 [55]. This is remarkable not only as we seek characteristic injury and pain makers but also as therapies are  explored. The Castaneda group asserts very rationally that NGFT/TrkA-targeting pathways are not only logical but also efficacious. Human trials involving anti NGF antibodies begun and listed on the clinicaltrials.gov site have been directed at chronic osteoarthritic pain and general low back pain. There were no studies to date that we could find that targeted acute skeletal injury or fractures. The central effect of NGF was explored by in vitro studies of cultured DRG neurons in which the neurotrophin in physiologic concentrations caused spontaneous actions potentials and significant changes in cytoplasmic Ca2+ concentrations. To further hone in on the mechanism of these electrodynamic and chemodynamic variations, the voltage gated Ca2+ channels were either inhibited or removed. Both maneuvers resulted in the cessation of the Ca2+ concentration changes. The group described a subpopulation of cultured DRG neurons (12 of 131;9%) that displayed large variations in depolarization amplitude when NGF was applied. Eighty percent of the NGF-responsive neurons or roughly eight neurons of the 131, responded to both capsaicin and the transient receptor potential voltage gated current channel super-agonist icilin; and the Ca2+ fluctuation was notably greater than in other nerve fibers. This indicates that NGF can activate TRP channels in nerves and render them hyperexcitable The fact that DRG, neurons can act as nociceptors and that they can respond to a molecule expressed shortly following PNI, suggests a rapidly responsive mechanism in the development of neuropathic pain [56]. The prospective use of anti-NGF in an attempt to prevent cancer-induced bone pain was explored using whole-brain functional connectivity  employing resting

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state functional magnetic resonance imaging in a murine model. A developing cancer pain state induced functional connectivity between ascending and descending pathways. The administration of monoclonal α-NGF antibody (mAb911) prevented this connectivity from occurring i.e. crosstalk between ascending and descending pathways such as the periaqueductal gray, the amygdala, thalamus, and cortical somatosensory regimes [57]. It is important to iterate that the increasing intensity or severity of cancer-induced bone pain that occurs with disease progression appears to be a continuance of the initial, acute NGF-mediated mechanism. The pathological sprouting and reorganization which has been demonstrated to generate and maintain chronic pain in other non-cancer pain syndromes appears to be at work in the malignancy pain-related setting. The murine model was used to demonstrate the fine course of the sprouting along with the evolution of chronic pain related behaviors (Jimenez-Andrade, 2010). The sprouting was noted to occur in sensory nerve fibers in close proximity to tumor-related tissue formation including inject cancer cells from a prostatic primary source, stromal cells and also from resultant osteoblastic activity. In this setting, another argument was made for the prophylactic use of anti-NGF antibodies. The group was able to demonstrate that not only does treatment with  anti-NGF antibodies prevent the pathologic sprouting, and decrease apparent cancer-related pain, but that the increase in injury-related expression and release of NGF is not mediated by nor the result of transcription activity by the cancer cells themselves, but by the tumor-associated stromal cells [58, 59]. This suggests a number of specific timed interventions that might be considered to combat this pain. For instance, we know that anti-NGF is efficacious in the combating of bone pain specifically because the periosteum is a TrkA receptor-rich environment. The upregulation of NGF may be inhibited in other ways, for instance translational silencing interventions using brief bursts of short hairpin RNA delivered via viral or bacterial vectors. In addition, small interfering RNA may be used in a similar fashion to accomplish the same translational interruption. Not only does anti-NGF act pre-emptively to inhibit nerve sprouting and TrkA binding in a murine model, it is also effective well into the disease process. Late blockade of NGF using anti-NGF antibodies at day 35, when neurite and major nerve sprouts had been documented was found to attenuate bone cancer nociceptive behaviors. In addition, the density of sprouted sensory and sympathetic fibers was noted to be decreased. This was thought to be attributed to the diminished half-life of tumor cells with accompanying cell death and necrosis of associated neural elements. This would have been followed by subsequent inhibition of new neurite and major nerve sprouts [60, 61]. The group also demonstrated that the receptor activator of nuclear factor kappa-B ligand (RANKL) also known among other names as TNF-related activation-induced cytokine (TRANCE), could be bound by the IgG2 monoclonal antibody denosumab and its osteaclastic effect inhibited. In addition to increasing bone density in treated patients with skeletal metastases, the antibody therapy also suggests a promising combination intervention to limit bone destruction and potentially minimize the subsequent NGF mediated neuropathic pain generated by this pathway [60, 62].

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The drivers of sensitization secondary to cancer pain are distinct and they are described as pure cancer pain and mixed cancer pain. In the former, tumor associated inflammation creates an acid-rich environment with subsequent, repeated discharge of nociceptors by molecular products of the inflammation including NGF. Here the sensitization occurs in the periphery and may give rise to secondary sensitization. The latter driver, mixed cancer pain, or cancer related axonal damage, is characterized by ectopic discharges in the somatosensory. This ectopic activity may create sensitization in the central nervous system, and in particular in the DRG [56, 63, 64]. A secondary or cascading effect was hypothesized by Tomotsuka et al. as they investigated induction of BDNF mRNA and protein in the murine DRG following intra-tibial inoculation of MRMT-1 rat breast cancer cells. They noted that BDNF was increased in small or nociceptive neurons as opposed to non-nociceptive neurons. Of additional interest, there was a significant increase in NGF expression, which is known to be a specific promotor of BDNF variants. The link was strongly suggested and indicated that not only is there a cascading effect but also an additive pain generating effect as well given the individual nocigenic actions of these two neurotrophins [65]. Pain created by tumors is not limited to osteoclastic events. Direct pressure by tumors on nerves and nerve roots may cause neuropathic pain as well. The relative density of Trk receptor expressing neurons is highest in the neuronal supply of the periosteum. It follows, then, that monoclonal antibody binding of Trk receptors as well as the NGF molecule are very effective in treating the pain generated by tumor invasion of bone. The effectiveness of α-NGF therapy on pain related markers and behaviors in a murine model was examined after randomization into placebo versus anti-NGF groups following the surgical application of sarcoma cells to their left sciatic nerves. Both groups were evaluated after 3 weeks with respect to chronic pain behavior. Dorsal root ganglia were resected, studied for calcitonin gene-related peptide, activity transcription factor 3, and immunostained for ionized calcium-­ binding adaptor molecule-1, (iba-1). Comparisons of chronic pain behaviors (mechanical allodynia) were made between the placebo and experimental groups and the behaviors were noted to be improved in the anti-NGF group. In addition, there was upregulation of CGRP and inmunoreactivity of ATF-3 in the dorsal root ganglia and spinal horn microglia in the placebo versus the anti-NGF group where the two measures were suppressed. The group concluded that in neuropathic pain secondary to direct compression of neural tissue by malignant cells there was some indication that anti-NGF therapy might be of value

Therapeutic Research Cannabinoid Receptors Cannabinoid receptors are typically inhibitory in nature and work via activation of the inhibitory G proteins, Gi and Go. This stimulation of CB receptors results in the

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inhibition of adenylyl cycled, activation of MAPK, inhibition of certain voltage-­ gated calcium channels and the activation of G protein-linked inwardly linked rectifying potassium channels (GIRK). In addition, cannabinoids have been shown to bind at TRPV1, α-7 nicotinic receptors and 5HT3 receptors. A summary of the location and activity of these channels is found in the table below and may serve to suggest other mechanisms or interactions mediated by cannabinoid binding. For instance, the 5HT3 receptor which binds serotonin, a ligand-gated ion channel. The 5HT3 receptor is found in both the central and the peripheral nervous systems. One study links binding of delta-9-tetrahydrocaabinol (THC) to peripheral cannabinoid (CB) receptors to NGF.  Specifically, the work by Wong et  al. in 2017 questioned whether intramuscular injection of THC could decrease NGF-induced sensitization in female rat masseter muscle. They chose this model based upon its mimicry of the symptoms of myofascial temporomandibular disorders. They determined peripheral expression of cannabinoid receptors immunohistochemically while using behavioral as well as electrophysiologic experiments to assess the functional effects of intramuscular injections of THC. The CB1 and CB2 receptors are expressed on trigeminal ganglion neurons that innervate both peripheral targets as well as the masseter muscle. Both CB receptors’ expression was significantly higher in TRPV1- positive ganglion neurons. The group found that 3 days following intramuscular injection of NGF, ganglion neuron expression of CB1 and CB2 was decreased. The expression of TPRV1 in these cells was unchanged. Regarding the behavioral limb of the experiment, they found that intramuscular injection of THF attenuated NGF-induced mechanical sensitization. No changes in mechanical threshold was found in the contralateral masseter muscles and no impairment of motor function after THC injection. In conclusion the group suggests that reduced inhibitory input from the peripheral cannabinoid system contribute to NGF-induced local sensitization of mechanoreceptors. They assert that activation of CB1 receptors by exogenous cannabinoids can provide effect analgesic relief without central side effects [66].

TrkA Inhibitors Antibodies to NGF are not the sole intervention available to treat the NGF axis. At least one other therapeutic approach has been tested to date. Merck has disclosed a urea-based TrkA inhibitor series, nonsymmetrical 1 (9H-fluoren-9-yl) urea and 1-(9H-xanthen-9-tl) urea derivatives that are targeting Trk-related conditions including chronic pain therapy. Disruption of TrkA function may also occur secondary to genetic anomalies [67, 68]. Indirect manipulation of NGF via its receptors, synthesis, degradation, and intracellular translocation offers an attractive approach to exploiting the role of this neurotrophin in managing neuropathic pain. The immunophilins FKBP51 and FKBP52 are co-chaperone proteins which are involved in controlling nuclear trafficking of glucocorticoid receptors (GR). They are encoded by the Fkbp5 and Fkbp4 genes [69]. In addition, FKBP51 has been shown to interact with phosphatases and kinases

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with resulting changes in protein phosphorylation and modification of signaling molecules [70]. The role of FKBP51 in neuropathic pain induced by chronic constriction injury was studied by Yu et al. in 2017when they knocked down FKB51 in a murine model and found that there was reduced production of pro-inflammatory cytokines (TNF-alpha, IL-1β, and IL-6); BDNF and NGF. This correlated with significant attenuation of mechanical allodynia and thermal hyperalgesia. The group also found that inhibition of FKBP51 suppressed the activation of NF-kappa B signaling in the DRG of CCI rats. In addition, the NF-kappa B inhibitor ammonium pyrrolidinedithiocarbamate (PDTC) also suppressed neuropathic pain indicator behaviors such a s withdrawal threshold and paw withdrawal latency in CCI rats [71]. NGF delivery to and maintenance at sites of peripheral nerve injury were studied using a novel tissue-engineering approach which employed a chitosan-sericin 3D scaffold. The components of the scaffold (chitosan and sericin) have both been reported to support Schwann cell growth and to improve nerve regeneration; while degradation products of the scaffold upregulate GDNF, EGR2 and NCAM expression in Schwann cells [72]. The authors also suggest that this might be of value in the treatment of chronic peripheral nerve injury. It appears that this approach would be of benefit in neuropathic disease processes in which the pain, hypersensitivity and hyperalgesia are thought to be due to dysfunction of NGF production or utilization as in DPN.

Small Molecule Antagonism of NGF Small molecules interact with NGF and inhibit the binding of the neurotrophin to TrkA and p75NTR. Unlike compounds which bind to the neurotrophin receptor itself, the small molecule class of inhibitors bind NGF non-covalently and alter the molecular topology and the electrostatic potential of the neurotrophin surface. Since discrete regions of NGF bind to TrKA and p75NTR, the NGFsmall molecule complex can no longer bind efficiently to these receptors [7, 73]. These discrete regions especially the loop regions of the NGF are highly variable and differ significantly from other neurotrophins [74, 75]. Small molecule technology has been explored in vitro and in vivo as a potentially efficacious intervention in the NGF-dependent mechanism of neuropathic pain development. These next-generation drugs can be administered orally, thus avoiding the need for injection and they are less expensive [76]. This fact leads us to consider the large capacity for chemical manipulation of small molecule structure in order to take advantage of the molecular topology of the neurotrophin. These small variants would likely continue to be orally active and economical to produce [76]. The small molecules, Ro08–2750, PD-90180, and ALE0540, bind in the I/IV cleft of NGF.  This is a segment which varies significantly among neurotrophins.

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The small molecule, Y1036 is a furan-based compound that has been demonstrated to contain a docking site which is in proximity to the glutamate 55 hydrophobic dimer interface. Among all the neurotrophins this site is highly conserved, but it is critical to p75NTR and TrKA [7, 73]. Another small molecule, ARRY-470, when administered early and sustained, inhibits sprouting and neuroma formation by sensory nerve fibers and reduced bone cancer pain-related behaviors. This Trk inhibitor has a 50: 1 plasma to CSF ratio; is a potent inhibitor of the tropomyosin kinase family of neurotrophin receptors. It demonstrates nanomolar cellular inhibition of TrKA (6.5 nM), TrKB (8.1 nM) and TrKC (10.6 nM). Arry-470 at 30 mg/kg significantly reduced thermal hyperalgesia mechanical allodynia in a rat CFA model of inflammation [77]. Small molecule-based technology has been touted as likely to bypass antibody-­ based therapies targeting NGF, especially with pan Trk inhibitors developed by Array pharmaceuticals e.g. Arry-470 and AR523 [75, 78]. Upon binding at the TrKA site, the NGF dimer initiates a cascade in which three tyrosines in the TrKA domain undergo autophosphorylation (Y670, Y674, and Y674). This enables auto phosphorylation of other tyrosines (Y490 and Y78 5) and triggers PI 3 k, Ras and phospholipase C-γ-1 which results in pain; and in vivo and in vitro, neurite outgrowth. In addition, there is also a rapid increase in expression of TRPV1 channels which is the result of the TrKA-mediated P13K pathway [79].  Therapeutic intervention sites also exist downstream of the NGF-TrKA interaction.  Potent inhibitors of TrKA kinase exist,  but selective ones are less easy to find [80]. In 2017 a novel pan-TrK inhibitor was reported that was shown to reduce pain in healthy male human subjects in high dose protocols and in comparison with ibuprofen and pregabalin. The pan-TrK inhibitor PF-06273340 is a peripherally restricted small molecule inhibitor of TrKs A, B, and C. It is equipotent at the three TrK receptors but is otherwise broadly selective; and was found to have analgesic effects in a wide range of pain stimuli in a double blind, placebo-controlled, five-period crossover study. PF-O6273340, in a 400 mg dose, was found to have a statistically significant benefit over placebo in an ultraviolet B heat pain detection test as it significantly reduced the hyperalgesia from the heat application. The study gave first evidence that a pan-Trk molecule can reduce hyperalgesia in human subjects [81, 82]. A novel NGF variant has been designed that selectively binds and activates p75NTR.  The variant (131R) has led to the hypothesis that it might be used to discriminate between NGFs two receptors. The variant is the result of substitution of a charged arginine for a hydrophobic isoleucine moiety with the resultant prevention of NGF binding to TrKA with preserved binding to p75NTR. The ease of manipulation at the 131 residue led the authors to speculate that specific targeting of the residue by small molecules may yield therapeutic options that have been yet unseen [83].

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Conclusion Neurotrophins are overexpressed in several debilitating conditions and include a variety of unique members to the neurotrophin family. These neurotrophins have been found to bind to a number of different receptors. NGF is one of the primary neurotrophic factors that has been found to be upregulated in vivo in times of inflammation and is involved in the transduction of pain. NGF promotes neuronal differentiation and neurite overgrowth. It is frequently present in increased blood titer in common ailments and chronic conditions including but not limited to: musculoskeletal disorders, diabetic peripheral neuropathy, migraine, interstitial cystitis, myofascial disease, prostatitis, and cancer-induced bone pain. In addition, NGF plays a role in the development of analgesia that can be seen in patients suffering from diabetic nerve pain. NGF is synthesized as a pro form, ProNGF, before becoming the mature form of NGF. It consists of two 13kDA subunits. NGF in turn, binds to receptors p75NTR and TrkA receptor with varying specificities and affinities, resulting in different physiological effects. The chronification of acute pain is a process that is highly robust and diverse in its presentation in the body. Manipulation of gene expression, and the various genetic routes that are undertaken regarding NGF play an essential role in this process. NGF is a vital component in hypersensitization via genetic modification in TrkA receptor expression and Na+ channels, respectively. Substance P (SP), plays an important role in the neuroendocrine system. It is secreted by inflammatory and neuronal cells. NGF induces and enhances the release of SP, as seen in murine modeling. NGF can also impact inflammatory cells, such as histamine producing mast cells, which also express the TrkA receptor. Interestingly, CIPA has shown a loss of NGF-TrkA-dependent and NGF-p 75 binding which has been attributed to a loss of deep pain perception. This absence of nociceptive sensory innervation iterates the impact of NGF upon the chronification of pain, due to a loss of function in NGFreceptor binding that exists this autosomal recessive disorder. Exogenous administration of NGF to the DRG in the streptozotocin-induced diabetic murine model reveals a correlation with an increase in hyperalgesia in mice. In human subjects, intramuscular injections of NGF increase the sensitivity of the fascia, especially in relation to chemical and mechanical stimuli. It is theorized that increased introduction of NGF has led to the progression of various musculoskeletal diseases. In patients suffering from IVD, the expression of NGF has led to an increased production of nociceptive cytokines in comparison to asymptomatic spinal discs, that do not produce this signaling molecule. In the urinary tract, NGF plays a primary role as biomarker in the differential diagnosis of chronic diseases such as IC, and OAB. NGF titers correlate with pain severity and its presence plays a role in the pathogenesis of various bladder ailments. In CIBP there is a possible linkage to the quantity of TrkA receptors, and the degree of pain severity experienced by patients.

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The impact of NGF on migraines remains ill-defined. Murine modeling involving migraine research has its limitations since it is quite difficult to recreate the microenvironment needed to display a human migraine, as biomarkers for migraine are not currently known. Studies have established that NGF and CGRP are both secreted during migraine attacks, and anti-NGF antibodies have been effective in reversing this upregulation. Cannabinoid receptors bind to a number of different receptors, including the TRPV1 receptor. TRPV1 and NGF work in tandem in order to induce inflammatory responses in the body. It is speculated that the use of Cannabinoid receptors may provide analgesic relief to patients suffering from NGF induced hypersensitivity. In addition to the use of NGF inhibitors, TrkA inhibitors may also be used to combat the chronification of acute pain. As of this writing, Merck™ has produced of a urea based TrkA inhibitor. The binding of NGF to TrkA leads to increased pain transduction, an anti-TrkA would be an emerging candidate for new therapeutic drug targets combatting chronic pain. Lastly, the use of small molecule antagonism of NGF, through non-covalent binding, inhibits NGF ability to bind to its primary receptors TrkA and p75NTR. Studies have been conducted in vivo and in vitro, which take advantage of the topology of the neurotrophin in an effort to create effective and economical therapeutic drug targets to reduce hyperalgesia and provide analgesic relief to patients suffering from chronic pain.

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55. Castaneda-Corral G, Jimenez-Andrade JM, Bloom AP, et al. The majority of myelinated and unmyelinated sensory nerve fibers that innervate bone express the tropomyosin receptor kinase A. Neuroscience. 2011;178:196–207. 56. Kitamura N, Nagami E, Matsushita Y, et al. Constitutive activity of transient receptor potential vanilloid type 1 triggers spontaneous firing in nerve growth factor-treated dorsal root ganglion neurons of rats. IBRO Rep. 2018;5:33–42. 57. Buehlmann D, Ielacqua GD, Xandry J, et al. Prospective administration of anti-nerve growth factor treatment effectively suppresses functional connectivity alterations after cancer-induced bone pain in mice. Pain. 2019;160(1):151–9. 58. Mantyh WG, Jimenez-Andrade JM, Stake JI, et  al. Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer pain. Neuroscience. 2010;171(2):588–98. 59. Jimenez-Andrade JM, Bloom AP, Stake JI, et al. Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain. J Neurosci. 2010;30(44):14649–56. 60. Pantano F, Zoccoli A, Iuliani M, et al. New targets, new drugs for metastatic bone pain: a new philosophy. Expert Opin Emerg Drugs. 2011;16(3):403–5. 61. Jimenez-Andrade JM, Ghilardi JR, Castaneda-Corral G, et al. Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain. Pain. 2011;152(11):2564–74. 62. Lozano-Ondoua AN, Symons-Liguori AM, Vanderah TW. Cancer-induced bone pain: mechanisms and models. Neurosci Lett. 2013. 557 Pt A:52–9. 63. Fallon M, Giusti R, Aielli F, et al. Management of cancer pain in adult patients: ESMO clinical practice guidelines. Ann Oncol. 2018;29(Suppl 4):iv166-iv191. 64. Mulvey MR, Rolke R, Klepstad P, et  al. Confirming neuropathic pain in cancer patients: applying the NeuPSIG grading system in clinical practice and clinical research. Pain. 2014;155(5):859–63. 65. Tomotsuka N, Kaku R, Obata N, et al. Up-regulation of brain-derived neurotrophic factor in the dorsal root ganglion of the rat bone cancer pain model. J Pain Res. 2014;7:415–23. 66. Wong H, Hossain S, Cairns BE. Delta-9-tetrahydrocannabinol decreases masticatory muscle sensitization in female rats through peripheral cannabinoid receptor activation. Eur J Pain. 2017;21(10):1732–42. 67. Schirrmacher R, Bailey JJ, Mossine AV, et al. Radioligands for tropomyosin receptor kinase (Trk) positron emission tomography imaging. Pharmaceuticals (Basel). 2019;12(1) 68. Bailey JJ, Schirrmacher R, Farrell K, et al. Tropomyosin receptor kinase inhibitors: an updated patent review for 2010–2016 – part II. Expert Opin Ther Pat. 2017;27(7):831–49. 69. Echeverria PC, Picard D. Molecular chaperones, essential partners of steroid hormone receptors for activity and mobility. Biochim Biophys Acta. 2010;1803(6):641–9. 70. Gaali S, Kirschner A, Cuboni S, et al. Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol. 2015;11(1):33–7. 71. Yu HM, Wang Q, Sun WB. Silencing of FKBP51 alleviates the mechanical pain threshold, inhibits DRG inflammatory factors and pain mediators through the NF-kappaB signaling pathway. Gene. 2017;627:169–75. 72. Zhang L, Yang W, Tao K, et  al. Sustained local release of NGF from a Chitosan-Sericin composite scaffold for treating chronic nerve compression. ACS Appl Mater Interfaces. 2017;9(4):3432–44. 73. He XL, Garcia KC. Structure of nerve growth factor complexed with the shared neurotrophin receptor p75. Science. 2004;304(5672):870–5. 74. Eibl JK, Chapelsky SA, Ross GM. Multipotent neurotrophin antagonist targets brain-derived neurotrophic factor and nerve growth factor. J Pharmacol Exp Ther. 2010;332(2):446–54. 75. Norman BH, McDermott JS. Targeting the Nerve Growth Factor (NGF) pathway in drug discovery. Potential applications to new therapies for chronic pain. J Med Chem. 2017;60(1):66–88. 76. Opar A. Kinase inhibitors attract attention as oral rheumatoid arthritis drugs. Nat Rev Drug Discov. 2010;9(4):257–8.

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Protein Kinase C and the Chronification of Acute Pain Benjamin Hyers, Donald S. Fleming, and Daryl I. Smith

Introduction According to the Institute of Medicine, over 100 million Americans suffer from chronic, long term pain, and in 2016 more than 42,000 people died from opioid overdose. While it is unknown exactly how many of these individuals were seeking to relieve chronic or neuropathic pain, we do know that 20% of patients presenting to physician offices with non-cancer pain symptoms or pain-related diagnoses receive an opioid prescription [1]. And in developing countries the 12 month prevalence estimates range from 2% to 40% [2]. Given the worldwide rise in the number of deaths from opiate overdoses from both heroin and prescription narcotics it is important to pay attention to this mechanism in the hope of gaining better understanding and insight into non-narcotic, non-traditional interventions that might stop chronic/neuropathic pain at or near its point of origin or in its cycle of sustenance. The data presented above lead us to consider the apparent under treatment of chronic pain. This under treatment is caused by a fundamental knowledge deficit regarding management of the cellular mechanism responsible for the development and maintenance of chronic pain pathways.

B. Hyers Icahn School of Medicine at Mount Sinai, Department of Anesthesiology, Perioperative, and Pain Medicine, New York, NY, USA D. S. Fleming University of Rochester School of Medicine and Dentistry, Medical Humanities, Department of Anesthesiology and Periopoerative Medicine, Rochester, NY, USA D. I. Smith (*) University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_2

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This chapter examines the role of protein kinase in the neuroplastic changes that convert acute pain to chronic pain. For this reason, we do not only look at PKC alone, but also at its interaction with other important molecules in the process. The concept of stabilizing a memory was discussed by Miyashita, et al in a 2008 work in which they speculated that a continuous and ongoing process was responsible for memory formation rather than a molecular cascade that tumbles to a specific stable endpoint. The stimulus-driven increase in the efficacy of synaptic transmission know as long-term potentiation (LTP) is a well-known phenomenon in the formation of memories. When it is observed at C- fiber synapses in the spinal dorsal horn, it is a model of pathological or neuropathic, chronic pain. At this level it is only induced by noxious stimuli, not by normal physiologic stimuli. LTP that occurs in less than 3 hours (early-phase LTP) requires activation of PKC, calcium/ calmodulin-dependent protein kinase II (CaMKII), phospholipase C and release of nitric oxide (NO). LTP that occurs after 3 hours in a murine model (late-phase LTP) requires de novo translation and activation of dopamine receptors or PKA; and brain-derived neurotrophic factor or ATP. Molecules and factors that promote spinal dorsal horn LTP (glial cell activation, cytokine overexpression) seem to inhibit hippocampal LTP [3]. We extend this concept and speculate that any new stimulus may be encoded. We may then for the sake of convenience refer to them collectively as events and describe them together.

Protein Kinase Families A brief overview of this enzyme reveals the existence of three PKC families: classical, novel, and atypical; and a total of ten known isoforms. Each family is represented in one or more components of neuropathic pain development. Table 1 reveals the organization of the families and their associated isoforms. The classical family consists of PKC alpha, beta, and gamma isoforms; the novel family consists of the delta, epsilon, eta, and theta isoforms; and the atypical family consists of the iota, lambda and zeta isoforms (Table 1). The role of PKC in the chronification of acute pain lies in its ability to effect synaptic plasticity. This has long been established, yet the specific mechanism beyond the phosphorylation event itself is not yet fully described. This is because there is a plethora of such events and these remain to be comprehensively and precisely delineated. What is known is that the metabotropic glutamate receptors (mGluRs) 1–8 modulate excitatory neurotransmission, neurotransmitter release, and therefore synaptic plasticity. PKC phosphorylates the intracellular terminus of mGluR5 at the serine 901 (S901) residue and this has been shown to block the binding of calmodulin, which is a dynamic regulator of mGluR5 trafficking. This decreases mGluR5 surface expression. Blocking the phosphorylation of mGluR5 at the S901 residue has been shown to affect mGluR5 signaling (Fig. 1).

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Table 1  Protein kinase organization by family and their associated isoforms Protein Kinase C Classical Requirements for activation Ca++ Diacylglycerol (DAG) Anionic phospholipid (Phosphatidyl serine) Isoforms α (alpha) β (Beta) γ (gamma)

Novel Atypical DAG (only) Neither Ca++ nor DAG

δ-Delta ε- epsilon η-Eta θ- theta C1- phospholipid binding C1 only C2- calcium binding + +

Domains (cysteine-rich) Activated by Phorbol esters (mimic DAG)

ι- iota λ-Lambda ζ-Zeta Partial, truncated C1 −

mGluR5

889

KST

Q RG HL

W

S901 CaM

K VI

P

Q RLSVHINKKEN PN QT S901 A CaM

917 P

PKC S901

CaM

Fig. 1  PKC phosphorylation of the intracellular terminus of the mGluR5 receptor at the serine 901 residue. Phosphorylation at this site blocks the binding of calmodulin and ultimately results in a reduction of mGluR5 surface expression and signaling

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In general, PKC phosphorylation of the neuronal cell surface occurs in the synaptic region. This is thought to be, in part, due to the increased autophosphorylation and thus activation of calcium/calmodulin-dependent protein kinase II which, in this case, leads to increased association of functional NMDARs at post-synaptic sites [4–10]. The PKC phosphorylation event also impairs the fast inactivation of heterologously-expressed Kv3.4 channels. When the channel “open-state” is prolonged it leads to an excitatory predominance which also allows excitotoxicity to develop [8]. The dynamic exchange of the receptor of the inhibitory neurotransmitter, glycine (GlyR) between synaptic and extrasynaptic locations via lateral diffusion within the plasma membrane has also been shown to be dependent, at least in part, upon PKC. This contribution is found in the interaction of the beta-subunit of the GlyR with the synaptic scaffold protein, gephyrin. Alterations of receptor-gephyrin binding are believed to shift the equilibrium between synaptic and extrasynaptic GlyRs and modulate the strength of inhibitory neurotransmission. There is a PKC phosphorylation site within the cytoplasmic domain of the beta subunit of the GlyR (residue S403) that causes a reduction of the binding affinity between the receptor and gephyrin. The result of this is an accelerated diffusion of the GlyR in the plasma membrane with a resultant diminution of these inhibitory receptors in the synaptic regions. PKC contributes to this form of maladaptive synaptic plasticity by disrupting an anti-nociceptive mechanism [11]. Following the theme of inhibitory glycinergic mechanisms that involve PKC activity, we turn our focus to the role of glial cells in pain modulation. In particular, the metabotropic glutamate receptor 5 (mGluR5) modulates addiction, pain, and neuronal cell death. When activated in primary microglial cultures by glycinergic agonists such as (RS)-2-chloro-5-­ hydroxyphenylglycine (CHPG), microglial activation in response to the inflammatory stimulus, lipopolysaccharide, is markedly reduced. In addition, microglial-induced neurotoxicity is also markedly reduced with CHPG treatment. Interestingly, the beneficial anti-nociceptive effects of mGluR5 activation are attenuated when PKC inhibitors and phospholipase C inhibitors are administered. This suggests that PKC also plays a role in the processing of antinociceptive mechanisms and, in particular, in the processing of inhibitory metabotropic glutamatergic receptors such as mGluR5 [12]. Protein kinase may also enhance plasticity by promoting synaptogenesis and synaptic maturation. This is an indirect promotion which involves activation of nerve growth factor (NGF); brain derived neurotrophic factor (BDNF); and the insulin-like growth factor 1 (IGF-1) which cause dendrite formation and neurite sprouting. Strengthening of synapses by PKC appears to be the result of the accumulation of PSD-95, following PKC-dependent phosphorylation, to the post-­ synaptic density (PSD) neuronal region. This phosphorylation occurs at the 295 serine residue. Elimination of the serine 295 residue in the PSD-95 abolishes this PKC-dependent membrane accumulation. Prolonged activation of PKC has been shown to double the number of synapses in murine adult hippocampal slice cultures, increase the number of synaptic vesicles, and to increase PSD-95 clustering in the synaptic regions in the same experimental models [13].

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PKC also plays a role in superoxide-induced hyperalgesia, a fact that based upon the suppression of this syndrome when a protein kinase C inhibitor is administered in a murine model [14].

Protein Kinase Isoforms and the Development of Neuropathic Pain While a number of individual PKC isoforms are uniquely associated with specific neuropathic pain syndromes this is not necessarily the rule. Diabetic neuropathic pain involves activation of a number of PKC isoforms. These are PKC -α, − β, −δ, and –ε. The downstream consequences of this isoform activation is the synthesis and the activation-initiation effect upon signaling proteins such as ERK and p38MAPK; cytokine expression, most notably TGF-β; cell cycle factors; and transcriptional factors such as NF-κB; and functional enzymes such as endothelial nitric oxide synthase; and sensitization of transient receptor potential channels. It is well known that the pathogenesis of diabetic neural injury involves the polyol pathway, advanced glycation end products, oxidative stress, protein kinase C activation, neurotrophism, and hypoxia. The transient receptor potential channels, TRPC, TRPM, and TRPV appear to be most responsible for the neuropathic pattern of diabetes. Protein kinases are important to the phosphorylation step that keeps the channel in its high activity state [15]. Taken together, PKC activity ultimately results in retinal, renal, neuronal, and/or cardiac complications [16].

Protein Kinase C Epsilon (PKCε) The phenomenon known as hyperalgesic priming is a plastic neuronal change which typifies the conversion of acute pain to chronic pain. It involves an inflammatory or a neuropathic insult which results in a response to the neuroinflammatory cytokine, PGE2. This response is PKCε epsilon-dependent, long lasting and hyperalgesic in nature. The nociceptor priming effect required approximately 72 hours to develop in a murine model [6, 17–21]. The “primed state” is believed to be generated via the PKC/ERK signaling pathway (Fig. 2). This theory asserts that the hyperalgesic priming signal is stored at the spinal cord level. The protein kinase, mammalian target of rapamycin (m-TOR), is required for the establishment of priming. In addition, it appears that the nuclear factor kappa B (NFκB) may play an important role in the development of protein kinase-mediated mechanical hypernociception. In a study by Souza et al., activation of NFκB signaling was determined by the translocation of the NFκB p65 subunit to the nuclei of DRG neurons. This was associated with persistent inflammatory hypernociception when triggered by PGE2 injection. This inflammatory hypernociception was blocked by dexamethasone as well as by the NFκB activation inhibitor,  ammonium pyrrolidinedithiocarbamate  (PDTC). Treatment with antisense oligonucleotides against the NFκB p65 subunit for 5 consecutive days also reduced

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Gs

NMDR

GPCR PGE2

EP–R

PKCa

Ca+2

PKCe

Priming

Fig. 2  This is a schematic representation of the priming-induced switch in the second messenger pathway of cytokine hyperalgesia. The switch is triggered by prostaglandin E2 as it acts upon the prostaglandin receptor, EPR. On the unprimed membrane, PGE2-induced hyperalgesia is mediated by a stimulatory receptor –activated G protein (Gs). Under “normal” circumstances G protein activates protein kinase A (PKA) which results in acute hyperalgesia (lower left neuron) and tightly regulated release of neurotransmitter. However, in the primed state PGE2 activation of EP-R receptors results in an additional pathway which involves Gi/o G protein which activates PKCε and results in prolonged, chronic hyperalgesia (depicted in the lower right neuron) with excessive, poorly regulated release of neurotransmitter

persistent inflammatory hypernociception. Inhibition of PKA and PKC epsilon reduced persistent inflammatory hypernociception which was associated with inhibition of NFκB p65 subunit translocation. This indicated that PKA and PKC played critical roles in the maintenance of persistent inflammatory pain [23]. PKC enhances NMDAR –mediated currents and promotes NMDAR delivery to the cell surface via synaptosome associated protein receptor (SNARE)-dependent exocytosis. PKC targets serine residue −187 as the phosphorylation site on the NMDAR and it also targets the synaptosome associated protein-25kDA (SNAP) for a phosphorylation event that is critical to synaptic membrane incorporation of NMDAR [24].

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Stress has been shown to cause hyperalgesia via both glucocorticoids, PGE2, and epinephrine and, interestingly, all three mechanisms include PKC as a final common pathway. At least one of these causes, the epinephrine stress response is thought to be due to a change in intracellular signaling pathways by which epinephrine sensitizes nociceptors and is believed to be the result of regulatory G protein coupled receptors switching from the stimulatory (Gs-analgesic action) to an inhibitory (Gi- non-analgesic) mode [25, 26]. Further, it has been shown that this switch is likely dependent upon a protein kinase C epsilon (PKCε) phosphorylation event. The exact mechanism of this is currently not known. Among the protein kinase C subtypes, epsilon (PKCε) demonstrated the highest upregulation in the chronic constrictive injury (CCI) murine model. Interestingly, it co-expressed with the transient receptor potential vanilloid type 1 (TRPV1) which appeared to cause the increased expression of interleukins and kinases responsible for channel sensitization [27, 28]. PKCε was critical to the phosphorylation event that maintained the TRPV1 in its high activity state. In addition, PKCε showed a complementary role in the maintenance of neuropathic pain [29].

Protein Kinase C Gamma (PKCγ) Primary afferent central terminals play a role in the first sensory synapse in a spinal nerve ligation (SNL) murine model of neuropathic pain. Increased d-glutamate release from primary afferents contributes to enhanced excitatory post synaptic current amplitude. PKC-related phosphorylation modifies trafficking of NMDARs and thus can lead to these electrical changes and excitotoxicity [30]. In another SNL, murine model pyruvate dehydrogenase kinase 1 (PDK) participates in the regulation of neuronal plasticity for central sensitization. Protein kinase C gamma (PKCγ) controls the trafficking and the phosphorylation of the ionotropic glutamate receptor. This control means that PKCγ participates in the initiation and maintenance of mechanical hypersensitivity in spared nerve injury. This also suggests that these interactions, both the phosphorylation of serine moieties on NMDARs and the mTOR-dependent PKCγ synthesis, may be viable targets for therapeutic intervention in the treatment of neuropathic pain. PKCγ also controls the trafficking and phosphorylation of ionotropic glutamate receptors in the murine spared nerve injury model [31, 32]. In the clinical setting, patients with opioid addiction who are receiving the narcotic drugs buprenorphine and methadone as maintenance therapy are known to experience hyperalgesia. Compton et  al. showed that heroin-dependent patients present to treatment in a state of hyperalgesia which is unchanged by the use of buprenorphine and methadone therapy [33]. The use of regional anesthesia can help avoid these issues. Regional anesthesia reduces the use of opioids in the perioperative period, decreases surgically induced pain sensitization, and provides better postoperative analgesia with fewer

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opiate-­related side effects, including OIH [34–36]. Interestingly, Méleine et  al. found that while regional anesthesia in rats can reduce both acute hyperalgesia and the development of chronic postoperative pain, there is a central sensitization that occurs with high doses of fentanyl. This high-dose fentanyl central sensitization is unaffected by the use of regional anesthesia [37]. Studies in a vulpine model demonstrated that central sensitization can develop within minutes of axotomy. An imbalance of inputs into adjacent regions of the sensory cortex occurs as interruption of the primary input e.g. (incisional axotomy) unmasks quiet, overlapping inputs into the regions from the periphery. The result is disinhibition of secondary inputs within minutes and with associated unchecked firing of these inputs and resultant neuropathic pain [38]. Both peripheral and central rationales exist for the development of neuropathic pain. The hyperexcitability of the dorsal horn neurons and interneurons along with the aforementioned apoptosis can account for the signs and symptoms complex with which our patient presented. This is compounded by a persistent opioid milieu which plays a somewhat more complex role in the symptomatology. The work of Rodriguez-Munoz et al., elucidates not only the mechanisms of neuropathic pain but also the possible mechanism of OIH that exists in our patient. In a 2012 study, this group elegantly described the colocalization of mu-opioid receptors in several CNS locations including the spinal dorsal horn (DH) and the periaqueductal gray (PAG) region [39]. Morphine is known to regulate-activate NMDA receptor (NMDAR) currents, and when PKCγ is incubated with the NR1 subunit of the NMDAR (C0, C1, or C2 termini) the mu-opioid receptor-NMDA receptor (MOR-­ NMDAR) colocalization is disrupted by PKCγ-mediated phosphorylation of a NMDAR associated C terminus. This phosphorylation leads to decreased internalization of the NMDAR with a concomitant increase of its Ca++ ion conductivity (Fig. 3). The result is increased NMDAR current and increased nociception. Conversely the effect of this dissociation on the MOR is increased internalization and recycling, however the recycling and subsequent antinociceptive effect fails to keep pace with NMDAR-mediated neuronal irritability and a net nociceptive predominance is created. In addition morphine has been shown to increase the expression of neuronal nitric acid synthetase which then stimulates the release of Zn++ which recruits PKCγ to the HINT protein at the MOR C-terminus and causes further MOR-NR1 separation [39]. Studies by Zalewski et al., (1990) and Garzon (2011) showed that Zn++ enhanced the affinity of PKC for phorbol esters or diacylglycerol, and stabilized the binding of PKC to the regulatory domain in the membrane thereby promoting prolonged PKC activation [40, 41].

PKC Delta (PKC δ) In a murine model of targeted knock-in mouse Sickle Cell disease (SCD), PKCδ was found to play a significant role in the development of pain associated with this disorder. The kinase was found to be elevated in the superficial laminae and

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a

NMDAR MOR

NR1

C2 C0

C–terminus

C1

b

NMDAR MOR

NR1

C2 C0

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C1 P

Phosphorylation PKC

Fig. 3 (a) Representation of the mu opiate receptor (MOR) and the n-methyl-d-aspartate receptor (NMDAR) in their stable, associated state in which they are bound at their respective C termini (Cx); and (b) in their unstable, dissociated, phos phorylated state following a phosphorylation event catalyzed by PKCγ). Increased NMDAR current and increased nociception ensues. Dissociation of the MOR is increases its internalization and recycling. The recycling and subsequent antinociceptive effect fails to keep pace with NMDAR-mediated neuronal irritability and a net nociceptive predominance is created

specifically in GABAergic inhibitory neurons where PKCδ was found to “inhibit the inhibitor” and thus generate spontaneous pain behavior and increased sensitivity in the knock-in mice. These changes were not observed in the control animals. The changes were attenuated by functional inhibition and neuron-specific silencing of

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PKCδ. Interestingly, in PKCδ-deficient mice with full establishment of the SCD phenotype, neither spontaneous pain nor evoked pain was detected [42].

PKM Zeta (PKC ζ) PKM zeta is an atypical PKC (aPKC). It can be expressed via activation of an internal promoter located within the full length of the PKM zeta gene resulting in a thwarted version of the enzyme that lacks the regulatory domain. This genetic omission results in a constitutively active enzyme [43]. Based upon this a number of subsequent studies have been performed that suggest that this variant plays a role in the maintenance of long-term synaptic strength. This was confirmed by the fact that treatment with the myristoylated pseudosubstrate inhibitor (mPSI) of atypical PKCs reversed previously established LTP [44]. The atypical PKC, PKMzeta is essential to the maintenance of the chronic pain state and its production is regulated in part by BDNF. PKMzeta contributes to the chronic pain state and also displays a number of the features of long-term potentiation (LTP) described above [45]. It is inhibited by the myristoylated protein kinase C-zeta pseudo-substrate inhibitor (ZIP) which, when administered in a murine model has been shown to reduce pain-related behavior as well as the activity of deep dorsal horn wide dynamic range neurons following noxious stimulation. These pain-related behaviors correlated with increased phosphorylation of PKCzeta/ PKMzeta in dorsal horn neurons. PKMzeta was found to be increased as a component of glutamatergic transmission in the ACC in rats with diabetic neuropathic pain. The streptozotocin-induced hyperglycemia murine model demonstrated increased presynaptic glutamate release and enhanced conductance of postsynaptic glutamate receptors. This correlated with increased phosphorylation of PKMzeta but not the expression of total PKMzeta. Again the addition of ZIP resulted in the attenuation of pain-related behaviors and the attenuation of the upregulated glutamate transmission [46]. PKM zeta maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC). Administration of a selective inhibitor, zeta-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation. This inhibition may be considered a possible therapeutic target but the specific molecular interaction of PKM zeta in the ACC remains speculative at this time. The role of PKM zeta in the spine has been demonstrated using a murine model. Following a plantar incision followed by intraplantar 90 injection used to simulate hyperalgesic priming, ZIP caused a significant decrease in spinal PKM zeta expression. Thus it appears that PKM zeta is responsible for the maintenance of peripheral inflammation primed neuropathic pain [22, 47–52]. PKC zeta and PKM zeta have been indirectly shown to contribute to neural hypersensitivity in the dorsal horn neurons. Inhibition of the kinases by ZIP reduces pain-related behavior in mechanical and thermal hypersensitivity without affecting acute pain or locomotor behavior in normal animals. Neither did ZIP inhibit mechanical allodynia nor did it inhibit hyperalgesia in neuropathic rats. The

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mechanism of the PKC zeta and PKM zeta sensitization is unclear but what is known is that ZIP inhibition results in a significant decrease in the expression of Fos in response to both formalin and complete Freund’s adjuvant (CFA) in both superficial and deep laminae of the dorsal horn [45]. One mesh point of nerve growth factor and PKC appears to be the NGF-induced rapid increase in the synthesis [53]. Treatment of isolated rat sensory neurons with NGF results in enhanced excitability. When siRNA targeted to PKM zeta was added to the culture, it reduced the expression of PKM zeta and also the NGF-mediated increased in the excitability of sensory neurons and the synthesis of the PKM zeta itself via a selective increase of translational expression of the kinase [53, 54]. Increased PKM zeta expression is also thought to be the source of hyperalgesia related to the infusion of the narcotic remifentanil and possibly other narcotics. Remifentanil is an opioid with a rapid onset and short elimination half-life. In a murine model, the increased nociceptive sensitization begins at 2 hours, peaks at 2  days, and was shown to return to normal nociceptive function at 7  days. Remifentanil hyperalgesia could be blocked by ZIP.  The NMDA blocker, Ro25–6981, attenuated mechanical and thermal hyperalgesia and reversed expression of PKM zeta and pPKMzeta. This suggests that GluN2B-containing NMDA receptor facilitated the development of RIH by controlling the expression activation of spinal PKM zeta in a murine model [55–57]. The development of RIH is believed to be a multifactorial process which occurs following opioid exposure in which there is an increased sensitization to nociceptive stimuli [56]. OIH has been known to occur with all opioids but, again, rapid onset and short elimination half-life have been associated with an increased risk of developing this syndrome [58]. The exact mechanism of how other narcotic-related hyperalgesias develop remains unknown and several theories have been proposed in the literature. One theory is that OIH may be caused by the activation of NMDA receptors and several studies have demonstrated that NMDA receptor antagonists decrease the risk of OIH [59]. Hong et al. showed that the NMDA antagonist ketamine decreased postoperative pain and the quantity of opioids used in gynecologic cases that used remifentanil [60]. Whether a decrease in remifentanil dose or the antagonism of the NMDA receptor causes a decrease in the development of OIH is currently unknown and the determination of this effect and elucidation of its mechanism must begin with in vitro studies with eventual progression to human clinical studies. Other theories for the mechanism of OIH include: inactivation of μ-opioid receptors [61], upregulation of the cyclic adenosine monophosphate pathway [62], and spinal dynorphin release [63–65]. An iteration of the essential role of PKM zeta was found in a 2015 work by An et al., in which a murine model of hyperalgesia priming was employed and specific inhibitors for PKM zeta (ZIP and Scr-ZIP) protein kinase Cs (NPC-15437). They found that following induction of hypersensitivity the PKM zeta inhibitor, ZIP, relieved the hypersensitivity (Scr-ZIP had no such effect). In comparison inhibition of PKC with NPC-15437 only prevented the initial, transient hyperalgesia. The group concluded that spinal PKCs contribute to the initial induction of persistent

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pain only; whereas PKM zeta plays an essential role in spinal plasticity storage, i.e., chronic pain and there is also a logical therapeutic target to control this syndrome. This has been restated in a number of works [47, 66–69].

PKC Epsilon (PKCε) The role of PKCε in neuropathic pain mechanisms has been elucidated by the behavior of this kinase in the presence of gabapentinoid drugs and agents, as well as its interaction with the excitatory amino acid transporter (EAAT) system. In a 2017 study, the efficacy of gabapentin on PKCε translocation in murine dorsal root ganglia was examined. The drug was shown to reduce PKCε the translocation event induced by bradykinin and prokinectin 2. At the time this was a novel mechanism of action for gabapentin, was found to be additive mechanism of action by acetaminophen. Thus it was proposed that the two drugs be used in combination. The effect of gabapentinoids (gabapentin and pregabalin), initially, was thought to be a direct action upon voltage-gated calcium channels (VGCCs), [70, 71] however the translocation of PKCε suggests that this may be an intermediary and, possibly, a requisite step in the mechanism of action of the anti-neuropathic pain component of gabapentin [72, 73]. The amino acid transport system has been found in recent years to be important in the regulation of nociceptive input into the central nervous system [74]. In a 2015 study by Gil et al., gabapentin was found to have an effect upon the activity of the excitatory amino acid transporter 3 (EAAT3) which regulates extracellular concentrations of the stimulatory amino acid glutamate in a Xenopus oocytes preparation. Gabapentin was found to decrease EAAT3 activity in a concentration-dependent fashion. Of note is that the PKC activator (phobol12-myristate 13-acateate, PMA) increased the activity of EAAT3. Pre-incubation of the oocytes with the PKC inhibitors chelerythrine, staurosporine or wortmannin decreased basal EAAT3 activity. Thus another protein kinase dependent therapeutic effect of gabapentin is seen, and perhaps equally important, this elucidates the pro-nociceptive effect of PKC as it is, conversely, to increase the extracellular concentration of the stimulatory amino acid, glutamate, and thus potentially contribute to neuronal excitotoxicity [73]. Gabapentin has also been found to have an inhibitory effect upon the PKC-­ ERK1/2 signaling pathway in the generation of visceral inflammatory pain in a murine model. Zhang et al., demonstrated that in the setting of formalin-induced inflammatory pain created by the intra-colonic injection of the substance, gabapentin intraperitoneal administration reduced visceral pain behaviors. These behaviors were also reduced following the injection of the PKC inhibitor, H-7, and the ERK1/2 inhibitor, PD 98059. Further, this group demonstrated that PKC membrane translocation (a critical component of a plastic change to chronicity) and ERK1/2 phosphorylation increased significantly following formalin injection. These effects were likewise reduced by the administration of gabapentin [75]. This work explains the

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value of gabapentin therapy in visceral neuropathic pain, but it also elucidates the role of PKC in visceral pain as well. PKC is also involved in the interplay of Toll-like receptor 4 (TLR4)-dependent microglia-mediated synaptic plasticity. TLR4 modulates GABAergic synaptic activities in the superficial spinal dorsal horn, and lipopolysaccharide (LPS) activation of TLR4 reduces GABAergic (inhibitory) synaptic activities via both pre-­ synaptic and post-synaptic activities. The mechanism involves LPS-mediated release of IL-1β from microglia, and the IL-1β suppresses postsynaptic GABA receptor activity activation of PKC.  There is also suppression of glial glutamate transporter activity that leads to a deficiency of glutamine supply and a critical decrease in GABA production which depends upon the glutamate-glutamine cycle [76]. PKC phosphorylation of the inhibitory extrasynaptic GABA (A) receptors, (GABA(A)Rs) plays a role in regulation of neuronal excitability. Again we see PKC as the inhibitor-of-the-inhibitor and thus the promoter of neuronal activity [77]. PKC is also involved in the interplay of Toll-like receptor 4 (TLR4)-dependent microglia-mediated synaptic plasticity. TLR4 modulates GABAergic synaptic activities in the superficial spinal dorsal horn, and lipopolysaccharide (LPS) activation of TLR4 reduces GABAergic (inhibitory) synaptic activities via both pre-­ synaptic and post-synaptic activities. The mechanism involves LPS-mediated release of IL-1β from microglia, and the IL-1β suppresses postsynaptic GABA receptor activity activation of PKC.  There is also suppression of glial glutamate transporter activity that leads to a deficiency of glutamine supply and a critical decrease in GABA production which depends upon the glutamate-glutamine cycle [76] (Fig. 4) [15].

Protein Kinase C and Novel Therapeutic Intervention Metalloproteinase Inhibition The matrix metalloproteinases (MMP-9 and MMP-2) are capable of degrading several types of extracellular matrix proteins and bioactive molecules. MMPs belong to a large family of zinc-dependent endopeptidases that contribute to the development of neuroinflammation through the cleavage and subsequent activation of extracellular proteins, cytokines, and chemokines [79]. MMP-9 and MMP-2 enhance neuronal transmission by phosphorylation of NMDA receptors, NR and NR2B in neuronal preparations; [80] and also that inhibition of spinal MMP-9 or MMP-2 can reduce symptoms of inflammation and neuropathic pain. In particular, the procyanidins, by virtue of their potent scavenging of reactive oxygen species, may be capable of depriving MMP-9/2 of their requisite activation molecules, i.e., the ROS [81]. In a 2016 study, Li et  al., described a novel therapeutic approach in which N-acetyl-cysteine (NAC). Both in vivo and in vitro application of NAC significantly

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IGF

IGF–1R

T–type channel

Ca+2

Gao

Gby

PKCa

GPCR PLC

ity bil ita xc re e p hy pe T–ty

iv i t act

y

elease Fr IG

inj u r y

© G. Hintz 2019

Fig. 4  A schematic representation of amplication of pain signals. Notice the role of phospholipase C (PLC) which catalyzes the hydrolysis of phosphatidylinositol 4,5 bisphosphate into the inositol trisphosphate and the protein kinase (PKCα) activating, diacylglycerol. Also depicted here are potential sites of PKC mediated intervention (red X’s), and the phosphorylation of ion channels that ultimately lead to increased, persistent activity or sensitization. IGF Insulin-like Growth Factor, IGF-1R Insulin-Like Growth Factor Receptor, GPCR G Protein Coupled Receptor, Gαo Receptor-activated G protein subunit alpha “other”, Gβγ: eceptor-activated G protein subunit beta, gamma, PLC Phospholipase C, PKCα Protein Kinase C alpha, Ca2+ Calcium ion [78]

suppressed the activity of MMP-9/2 with a resultant postponement of the occurrence of neuropathic pain, but also the maintenance of chronic constrictive injury (CCI)-induced injury in a murine model. This effect was believed to be three-fold in nature, first via blockade of the maturation of IL-1β, a critical substrate of MMPs; second, via inhibition of phosphorylation of PKCγ, NMDAR1, and nitrogen-­ activated protein kinases; and third by inhibiting chronic constrictive injury (CCI)induced microglial activation [82].

Flavonoids Flavonoids are water soluble, secondary plant metabolites that fall into the polyphenol class of molecules. They are divided into six groups; flavones, flavonols, flavanones, isoflavonoids, anthocyanins, and chalcones. In a 2010 study by Hagenacker et al., the flavonoid myricetin was shown to have an anti-analgesic effect in a murine model of spinal nerve ligation (SNL) neuropathic pain. Analysis of voltage-­activated calcium channel currents in the dorsal root ganglion and the stimulating influence

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of p38 mitogen-activated protein kinase (p38) or PKC revealed that myricetin reduced mechanical allodynia and thermal hyperalgesic for several hours. There  is a paradoxical effect, i.e., increase in voltage activated calcium channels. This effect was blocked by inhibition of p38 but not by inhibition of PKC [83]. Also of interest is the fact that in another murine model of inflammatory neuropathic pain, myricetin inhibited cytokine-induced phosphorylation of p38 in the spinal cord and prevented activation of PKC following injection of phorbol-myristate acetate. Myricetin may directly inhibit the activating phosphorylation event that PKC itself undergoes [84]. In another study, chemotherapy-induced peripheral neuropathy and mast cell and basophil degranulation, the flavonoid quercetin was found to inhibit histamine release caused by the drug, paclitaxel. A murine model was used and it showed that pretreatment with quercetin inhibited histamine release in a dose-dependent fashion and raised the thresholds for heat hyperalgesia and mechanical allodynia. Quercetin also suppressed the paclitaxel-induced increase in PKCε and TRPV1 expression in the spinal cord and DRG. In the same study the authors found evidence that quercetin inhibited the translocation of PKCε from the cytoplasm to the neuronal membrane in the spinal cord and DRG [85].

Chelerythrine The antibacterial agent chelerythrine is also a potent inhibitor of PKC. It is a benzophenanthridine class alkaloid (Fig. 5). It has also been shown to have anti-cancer properties by virtue of its ability to cause apoptosis. This unfortunately can occur in a less than specific manner that can involve both malignant and non-malignant cells. This has led to the development of a series of novel chelerythrine analogues which have more specific, dose-dependent G0/G1 cell cycle arrest in non-small-cell lung cancer and other cancer cell lines while exhibiting minimal toxic effects on non-malignant cells [86]. half-maximal inhibition of the kinase occurs at 0.66 micromoles. The molecule interacts with the catalytic domain of

Fig. 5  The antibacterial agent chelerythrine. It interacts with the catalytic domain of PKC and is a competitive inhibitor with respect to ATP

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PKC, is a competitive inhibitor with respect to ATP. PKC can be controlled through this site via phosphorylation of serine/threonine and tyrosine residues that influence enzyme stability, protease/phosphatase resistance, protein-­protein interactions; subcellular targeting and overall enzymatic activity [87, 88]. PKCγ plays a role in a number of neuropathic syndromes. These include migraine headaches and chronic pancreatitis. In both settings it appears that phosphorylation of the GluR1 subunit is the critical component in receptor activation that establishes the excitotoxic environment. Moreover, in both instances the PKC inhibitor chelerythrine relieved allodynia in murine models with observed reduction in the phosphorylation of receptor subunits. In a study by Wei et al., noradrenaline acting in the ventrolateral orbital cortex was found to reduce allodynia caused by spared nerve injury in a murine model. It is interesting to note that in this setting PKC signaling leads to activation of descending inhibitory pathways that decrease nociceptive transmission at the spinal cord level. Here chelerythrine has the opposite effect and suppresses the anti-allodynic effect of PKC [89].

IL-10 Manipulation via Viral DNA Transduction Genetic manipulation as a therapeutic approach to treating neuropathic pain was explored via the use of a herpes simplex virus (HSV) vector in a study by Thakur et al. In this work they found that continuous delivery of IL-10 blocks the nociceptive and stress response in the DRG by reducing IL 1β expression and also by inhibiting the phosphorylation of p39\9 MAPK and PKC. This study also showed that continuous expression of IL-10 also altered Toll-like receptor expression in the DRG.  The reduction of a number of proinflammatory cytokines and associated stress markers indicates that this technique may hold promise as a means of treating neuropathic pain [90].

Upregulation of Parvalbumin Interneurons Parvalbumin (PV)-expressing interneurons produce GABA and glycine and are activated by Aβ fibers [91, 92]. They are inhibitory interneurons and in naïve and neuropathic pain conditions they contribute to the regulation of noxious input reaching the central nervous system. Ablation of these neurons results in disinhibition of PKCγ excitatory interneurons, while activation of these same neurons alleviates mechanical hypersensitivity in the murine model [93]. For our purposes we focus upon the genetic upregulation of these cells. This has been accomplished using a modified Gq-coupled muscarinic receptor (M3D) that responds only to clozapine N-oxide (CNO), a blood brain barrier permeable synthetic agonist. Binding of CNO to the M3D receptor in vitro generates action potentials (inhibitory) in PV interneurons. The in vivo ac activation of PV interneurons involves the injection of the lumbar spinal cord with an adeno-­ associated viral (AAV) vector that expresses M3D.  This results in the establishment of an increased receptor titer in the PV interneuron. Subsequent administration of CNO results in attenuation of mechanical allodynia and mechanical hypersensitivity without affecting thermal sensitivity.

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To iterate, PV interneurons target excitatory PKCγ and are anatomically positioned to do so. Genetic upregulation of these interneurons may prove potentially effective therapeutic interventions [93].

Manipulation of DGK Activation of C1 domain proteins such as PKC under normal physiologic conditions is accomplished by diacylglycerol (DAG) and its analogues. Inactivation of these proteins would be one therapeutic goal of treating neuropathic pain. The phorbol analogue, phorbol 12-myristate 13-acetate (PMA) increases the mean frequency of spontaneous postsynaptic currents (sPSCs) in dorsal horn neurons. This is believed to be due to subsequent phosphorylation of voltage-dependent calcium channels (VDCC) by PKC [94]. DAG is found in the neuronal synaptic region. It is a signaling molecule that is generated by the activation of several different surface receptors. These include metabotropic glutamate receptors as well as NMDA receptors. DAG is a requirement for activation for both the classical (α, β, γ) and the novel (δ, ε, η, θ) families of protein kinase C, but not the atypical family (ι, λ, ζ). It is responsible for supplying the phosphorous in the phosphorylation of the C1 domain in a fashion similar to the phorbol esters [95]. DAG signaling is terminated by conversion of DAG to phosphatidic acid (PA) by diacylglycerol kinases (DGK). A study by Yang et al., in 2013 examined how DGKs are targeted to subcellular sites of DAG generation. They established that postsynaptic density (PSD)-95 family proteins interact with and promote synaptic localization of the iota subtype of DGK (DGKiota). DGKiota also acts presynaptically. Generation of synaptic DAG is triggered by the action of diverse surface receptors including N-Methyl-D-aspartate (NMDA) receptors and metabotropic glutamate receptors [94]. Interference with the phorbol-dependent activation of PKC pathway was observed as a mechanism for preventing inflammation induced by carrageenan, bradykinin, and prostaglandin E2, epinephrine, liposaccharide, or complete Freund adjuvant by benzofuranone (BF1). The 3-aryl-benzofuranone compounds are known strong scavengers of oxygen-centered and carbon-centered free radicals. Specifically, BF1 inhibited neuropathic pain behavior in a murine model [96]. Further evidence of the role of PKC in the hyperalgesia that is induced by free radicals is found in a study by Kim et al., in 2009. It is known that at least two reactive oxygen species (ROS), nitric oxide (NO) and superoxide (O2−) contribute to persistent pain. Following hyperalgesia created by spinal nerve ligation, the removal of O2− by the heterocyclic compound, 4-hydroxy-2,2,6,6-tetromethylpiperidin-1-oxyl (TEMPOL); or inhibition of NO production by nitroarginine methyl ester (l-NAME) reversed the neuropathic behavior in a murine model. It is clear that these ROS act by separate mechanisms to generate pain. Only superoxide hyperalgesia was suppressed by inhibition of PKC [14]. PKCγ activation is important to the development of mechanical allodynia. Genetic and pharmacologic impairment of PKCγ prevents mechanical allodynia in

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a number of animal modes of pain following nerve injury or reduced inhibition. Pham-Dang et al., tested the role of phorbol esters directly in this mechanism when they performed intracisternal injection of 12,13-dibutyrate (a phorbol ester) and observed the induction of static and dynamic mechanical allodynia in a 2011 work. Activation of both lamina I-outer lamina II, and IIi-outer lamina III neurons was observed. In particular, this activation included lamina IIi- PKCγ-expressing interneurons which, again, occurred in direct conjunction with the development of mechanical allodynia. This mechanical allodynia and the associated activations were all prevented by inhibition of PKCγ with KIG31–1 [97]. The inflammatory peptide, bradykinin exerts modulatory actions upon glutamatergic receptors in superficial dorsal horn neurons via pre-and postsynaptic bradykinin receptors, B(2). B(2) receptors are coexpressed with PKA and PKCγ. Bradykinin can augment AMPA and NMDA receptor-mediated excitatory currents in lamina II neurons. This  augmentation requires coactivation of both PKA and PKCγ and it triggers the ERK cascade that results in thermal hyperalgesia in an in vivo murine model. Inhibition of ERK, PKA, or PKCγ reduces this thermal hyperalgesia. Bradykinin generates pain hypersensitivity by activating several kinases in the dorsal horn and these include PKCγ as an important mediator [98]. The upregulation of the plant DGK gene, e.g., in maize, occurs under conditions of drought, salt and cold stress and the downregulation of DGK genes during salt stress rectification suggests that specific genetic modulators exist that may be found in or applied to mammalian systems [99, 100]. There are a number of mammalian DGKs within the zeta subtype (DGKzeta) that localize to neuronal synapses by associating directly with the postsynaptic scaffolding protein, PSD-95 and regulating dendritic spine maintenance by promoting DAG to PA conversion. In 2012, Seo et al., demonstrated a role for DGKzeta in the regulation of synaptic plasticity in the hippocampus. They showed that DGK (via a decrease in DAG) promotes long term depression (LTD) at its respective synapses and involves both NMDA receptors and metabotropic glutamate receptors. The work also indicates that DGKzeta regulates hippocampal long term potentiation and LTD by promoting conversion of DAG to PA [101]. The existence of this phenomenon in the hippocampus via a DGK-dependent DAG –PA mechanism that is similar to what is observed at the spinal level, leads to the logical speculation that a similarly generated plasticity occurs at this peripheral site. The means by which the limiting step of PKC activation during the period when pathologic plastic changes are most likely to occur (often within 2–3 hours of the noxious insult) may present the largest part of the challenge to manipulating this step. Temporal considerations, i.e., the question of when and for how long to intervene standout. Figure 6 illustrates some of the critical relationships in this consideration as well as some of the potential points of intervention. In particular, it shows the interaction of DAG phosphorylating PKC to activate and liberate the molecule for translocation towards the synaptic vesicle on  the pre-synaptic membrane; and towards the PSD-secured NMDA and AMPA receptors for modification, i.e., plastic changes, on the post-­ synaptic membrane.

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PA

Protein Kinase C and the Chronification of Acute Pain

GPCR

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P

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DAG PA

PKC

D

AG

A G

D

PO4

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G

NMDAR

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AMPAR

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A D

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G PA

Fig. 6  The DAG phosphorylation of PKC to activate and liberate the molecule for translocation towards the synaptic vesicle on the pre-synaptic membrane; and towards the PSD-secured NMDA and AMPA receptors for modification, i.e., plastic changes, on the post-synaptic membrane. This figure illustrates some of the critical relationships in this consideration as well as  some of the potential points of intervention

The question of therapeutic targeting of DAG and DGK as a critical step in the plasticity development mechanism is raised. DAG induces PKC activation. This is illustrated in Fig. 6 in which DAG is noted to be active in both the pre- and postsynaptic membranes, activating PKC and playing its crucial role in neurotransmitter release as it phosphorylates the munc-13 protein which comprises part of the cellular structure which anchors synaptic vesicles [102]. Blanket inhibition of PKC, i.e., use of a systemic inhibitor of the kinase would no doubt cause unacceptable adverse events because of the ubiquitous function of protein kinases throughout the nervous system. However, directed, synapse population-specific modulation of DGK with strict temporal control of the initiation and termination of the upregulation holds promise in a theoretical sense. Upregulation of the DGK gene, as mentioned above, would remove, at least temporarily, the substrate, DAG, needed to activate PKC and thus initiate the sensitization cascade. This might be accomplished via genetic manipulation via viral (HSV) DNA transduction as in the case of IL-10 above. Although in this case, the genetic material would be the diacylglycerol kinase zeta [Homo sapiens] gene, DGKZ. The transduction vehicle would carry the induced

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gene with a limiter sequence to the involved spinal level(s) where the time-limited, continuous increased production of DGKzeta would attenuate PKC activity by regulating DAG levels in the intracellular signaling cascade and in signal transduction [90, 103].

Manipulation of Store-Operated Calcium Channels Activation of Orai1, the gene which codes for calcium release-activated calcium channel protein 1 (CRAC1), is a key component of the store-operated calcium channels (SOCs) and is also important in neuronal excitability. SOCs mediate important calcium signals in non-excitable and excitable cells. Activation of Orai1, with subsequent expression of CRAC1, increased neuronal excitability via the protein kinase C- extracellular signal-regulated protein kinase (PKC-ERK) pathway in dorsal horn neurons. Orai1 deficiency decreased acute pain induced by noxious stimuli, nearly eliminated the second (late) phase of formalin-induced nociceptive response, markedly attenuated carrageenan-induced ipsilateral pain hypersensitivity; and abolished carrageenan-induced contralateral mechanical allodynia [50]. While the intrigue of genetic manipulation of Orai1 exists here, as a therapeutic target it is also logical to consider the effect of specific PKC manipulation and/or inhibition upon this pathway as well, especially in light of the Kv3.4-containing A-type potassium channel and its regulatory impact upon neuronal excitability [8].

Manipulation of Purinergic Receptors The purinergic receptor, P2X7 R plays an important role in the extracellular, ATP-­ dependent release of the NMDA coagonist, d-serine. In 2015, Pan et al., loaded tritiated ([(3)H]) d-serine into astrocytes then stimulated the release of the [(3)H] d-serine using ATP and the potent P2X7 R agonist, 2′(3′)-O-(4-benzoylbenzoyl) adenosine-5′-triphosphate (BzATP). This same release was abolished by selective P2X7 R antagonists and by shRNAs. The role of protein kinase C in this mechanism became clear when the group added the PKC inhibitors chelerythrine, GF109 203X and staurosporine and was able to inhibit the P2X7R-mediated serine release. This did not occur when the Ca++ − dependent PKC inhibitor Go6976 was administered. They concluded that P2X7 R- d-serine release is an important mechanism for activity-­dependent neuron-glia interaction, and it is also shown by their work that this mechanism of activity-mediated synaptic plasticity is PKC dependent [104]. Protein kinases also affect the adenosine 2A metabotropic receptor (A2AR). When agonized in a murine model, these receptors have produced a prolonged reversal of allodynia in a chronic constrictive model of neuropathic pain. When administered with a known proinflammatory substance, such as lipopolysaccharide, to

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neonatal microglia and astrocytes, the A2AR agonist ATL313 attenuated TNFα production. Interestingly ATL3 13 had no effect on the anti-inflammatory cytokine, IL-10. The ATL313-mediated attenuation of TNFα release effect was reversed by PKC in vitro and both PKA and PKC inhibitors significantly reversed the effect of the A2AR agonist on neuropathic allodynia. This leads to the logical suggestion that A2AR agonists may prove a novel target for neuropathic pain treatment [105]. Another purinoceptor influenced by PKC is the ATP-gated P2X receptor cation channel, P2X3. Agonism of these receptors evokes voltage-gated sodium channel (VGSC) DRG neurons in neuropathic conditions. In a 2011 work by Mo et al., it was demonstrated that P2X3 purinoceptor-mediated currents induced by α, β meATP resulted in activation of TTX-sensitive VGSCs in neuropathic nociceptors. It is important to note that this was not observed in non-neuropathic nociceptors. When the group added the PKC inhibitors staurosporine or calphostin C, the α, β meATP-induced sodium channel activity was decreased which coincided with reversal of neuronal hypersensitivity. This implicates PKC as a mediator in the post-­ neural injury upregulation of VGSC activity initiated via agonism of the P2X3 purinoceptor [106].

Appendix Element PKCγ IL-1β

Comments/Characteristics Visceral pain IL-1beta reduces glial glutamate transporter activities through enhancing the endocytosis of both GLT-1 and GLAST glial glutamate transporters. TRPV1 Sensitization Critical role in generating/maintaining sensitivity produced by NGF PKMζ Critical for maintenance of hippocampal LTP Only molecule implicated in perpetuating L-LTP maintenance. Autonomously active, aPKC isoform; necessary/sufficient to maintain LTP and long-term memory PKCε Inhibition of PKCε reduced persistent inflammatory hypernociception, Hyperalgesia and priming are PKCε and G(i) dependent; transition from acute to chronic pain, and development of mu-opioid receptor tolerance and dependence linked by common cellular mechanisms in the primary afferent IGF and IGF-1 receptor activation after nerve injury enhances T-type channel current and PKC DRG excitability; recruits a Gβγ-dependent PKCα pathway Phorbol Activates C1 domain proteins on PKC → Phosphorylation of Voltage Dependent Ca++Channels (VDCC) NMDA-R Possesses ion channel characteristic; activity is modulated by phosphorylation of NR1 DGKs Converts DAG to Phosphatidic acid (deactivates); requires PSD-95 proteins for synaptic localization; regulates DAG signaling/ neurotransmitter release in LTD. Bradykinin Activates multiple kinases in dorsal horn → Potentiates Glutamatergic mediated hypersensitivity

48 Element BDNF

EAAT3 GABA-R

B. Hyers et al. Comments/Characteristics Binds specific TrkB receptors Mediates PKMζ (and PKCλ) Regulates PKMzeta, and aPKCs Maintains centralized chronic pain state. Critical role in initiating and maintaining persistent sensitization Occurs via a ZIP-reversible process. Controls synaptic PKMζ and PKCλ synthesis via mTORC1 and BDNF enhances PKMzeta phosphorylation Sustains L-LTP through PKMzeta in a protein synthesis-independent manner Promotes neuronal growth, development, synaptogenesis, differentiation, survival and neurogenesis following nerve injury (Excitatory amino acid transporters)- Activity leads to re-uptake of AA neurotransmitters and” turn off” noxious impulse. Activity inhibits nociception but increased PKC decreases GABA activity

Summary chart of potential PKC-mediating therapeutic elements Inhibitors Procyanidins Chelerythrine

Quercetin (polyphenolic flavonoid)

Melatonin IL-10 Myricetin(flavonoid) AP5 (2-amino-5-­ phosphopentanoic-acid) DGKζ ZIP BDNF inhibitor Pregabalin/gabapentin Bisindolylmaleimide

Comments Suppress matrix metalloproteinase and reduce phosphorylation of PKCγ Prevented protein kinase C activation in the hind paw after intraplantar injection of phorbol-myristate acetate Attenuates remifentanil induced thermal and mechanical hyperalgesia Inhibits translocation of PKCepsilon from the cytoplasm to the membrane in the spinal cord and DRG of paclitaxel-treated rats. Inhibits excessive histamine release from paclitaxel-stimulated RBL-2H3 cells in vitro, suppressed the high plasma histamine levels in paclitaxel-treated rats. Raises thresholds for heat hyperalgesia and mechanical allodynia in paclitaxel-treated rats and mice. Suppresses increased expression of PKCε and TRPV1 in SC and DRG (paclitaxel-murine) Inhibit PKCγ and NR1 activities in the spinal cord. Decreases the expression of IL-1β and inhibits PKC phosphorylation. Inhibited phosphorylation of p38 in the spinal cord induced by intrathecal cytokine administration AP5 reduces the amplitude of monosynaptic EPSCs evoked by dorsal root stimulation. Blocks GluN2A-containing NMDARs (murine) Terminates DAG signaling by converting DAG to Phosphatidic acid Microinjection into ACC attenuates upregulation of glutamate transmission and painful behaviors in STZ-injected rats. Inhibition of PKMzeta reversed BDNF-dependent form of L-LTP Gabapentin decreased EAAT3 activity in a concentration-­ dependent manner. Inhibitory effect on the PKC-ERK1/2 signaling pathway PKC inhibitor. Attenuates status epilepticus-induced reactive astrogliosis.

Protein Kinase C and the Chronification of Acute Pain Inhibitors GF109203X Stuarosporine

49

Comments General protein kinase C (PKC) inhibitor. Possibly used to prevent the conversion from acute to chronic pain General protein kinase C (PKC) inhibitor. Possibly used to prevent the conversion from acute to chronic pain

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Tumor Necrosis Factor-Alpha and the Chronification of Acute Pain Daryl I. Smith and Hai Tran

Tumor necrosis factor- alpha, (TNFα), can sensitize nociceptors. It can induce those sensory neurons to further express receptor components capable of transducing extracellular TNFα. In a three step interaction, Kagan et al. in a 1992 work described the insertion of TNFα into a cell membrane where it formed its own ion channel as part of the inflammatory response to neural injury. The insertion was observed into the hydrocarbon core of the phospholipid bilayer and was inversely related to pH, i.e., the insertion rate increased with decreasing pH. It has also been shown to induce oligodendrocyte necrosis, myelin dilatation, and periaxonal swelling which opens Na+ channels [1]. Further studies showed that addition of TNFα to human histocytic lymphoma cell culture preparation increased Na+ uptake by 100–300% in the presence or absence of the Na/K-ATP are (Na-K+ pump) inhibitor oubain which reinforced de novo creation of Na+ channel theory. Interestingly, activated macrophages generate an acidic micro environment, [2] a setting which would support the insertion of the expressed TNFα into the target tissue membrane and another step forward sensitization. The sensitization also occurs centrally. Following neural injury and the concomitant inflammatory insult there is a rapid increase in expression in TNF receptor 1 (TNF-R1) as a result of the excitation-translation coupling. This allows the retrograde transport of TNF-α at a minimal velocity of 2–2.5  mm/h and results in a transient rise in the TNF-R1 expression in the DRG where the central sensitization occurs. Of therapeutic interest is the fact this retrograde transportation of TNF-α is directly inhibited by the local anesthetic bupivacaine, the neurotoxin tetrodotoxin, and the anti-mitotic drug colchicine [3, 4].

D. I. Smith (*) University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA e-mail: [email protected] H. Tran URMC Strong Memorial Hospital, Department of Anesthesiology and Perioperative Medicine, Rochester, NY, USA © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_3

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The addition of TNFα to human histocytic lymphoma cell culture preparation, for instance, increased Na+ uptake by 100–300% in the presence or absence of the Na/K-ATP are (Na-K+ pump) inhibitor oubain which reinforced de novo creation of Na+ channel theory. Activated macrophages generate an acidic micro environment [2]. This setting supports the insertion of the expressed TNFα into the target tissue membrane and another step toward sensitization. TNFα is indicative of the inflammation following nerve injury that is important to the development of pain [5]. Not all painful stimuli results in the expression of TNFα. In 2010, Frieboes et al., examined other markers of peripheral stimuli, c-fos and Nav1.8 channel titers, in the setting of chronic nerve compression in an animal model. The group used Sprague-­ Dawley rats and applied chronic compression to the sciatic nerve. They measured c-fos, TNFα, IL-1, and Nav1.8 channels in adult Schwann cell cultures and found that while c-fos and Nav1.8 channels increased, signs of painful stimuli and sensitization; TNFα and IL-1 titers did not. This led to the conclusion that increased TNFα and Il-1 activity was a consequence of acute injury which led to sensitization and neuropathic pain but  was not a component of chronic neural painful stimulation with resultant neuropathic pain [5]. Classically, the cascade of molecular events that lead to the neural injury- mediated expression of TNF-α is initiated by the stimulation of the toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS), i.e., debris from an injured cell membrane. Binding at the surfaceTLR4 receptor, LPS triggers the activation of interleukin −1-receptor associated kinase 1 (IRAK-1), which is a molecular degradation step. This leads to the mitogen-activated protein kinase (MAPK) phosphorylation of extracellular receptor-activated kinases ½ (ERK1/2), the p38 MAP kinase, [6] the c-jun N-terminal kinases; and the activation of NF-kappaB. Both of these pathways end in the expression of TNF-α [7]. From study of the cellular injury -triggered cascade to cytokine expression, we understand the critical role of the toll-like receptor. Antagonism of this receptor was examined in two recent (2019) studies. In the first, the peptide antagonist of TLR-4 (PAT) was shown to radically reduce TNF-α, IL-1β and IZ-6 expression and ROS production in the presence of LPS stimulation in a murine model [8]. In the second paper, the TLR4 antagonistic peptide 2 [TAP2] decreased mRNA levels of TNF-α, IL-1β, IL-6, COX2 and iNOS. By 54–83%. This correlated with a decrease in neuropathic pain behavior the authors concluded that TAP2 efficiently mitigates neuropathic pain behavior by suppressing microglial activation [9]. In a 2010 study, Cheng et al., demonstrated an upregulation of TNF-α and other inflammatory mediators including cyclooxygenase (COX)2 and inducible nitric oxide synthases (iNOS) in the lumbar dorsal root ganglia of a murine model. In this work, they specifically found that an antibody against nerve growth factor (NGF) inhibited p38 phosphorylation which, as shown by Tazi et al., above, [7] is one of the precursor steps to TNFα expression. These authors concluded that NGF must therefore be an upregulating factor for TNF-α [10]. The synthesis of TNF- α results initially in a 26 kDa type II transmembrane protein that assembles into a homotrimeric molecule (tmTNF). The matrix metalloproteinase, TNFα-converting enzyme (TACE/ADAM17) generates soluble TNF

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homotrimers (sTNF; 51 kDa). TNF receptor factors, type1 and type 2, (TNFR1 and TNFR2) bind TNF. These receptors contain four cysteine-rich domains (CRD) in their extracellular domains. The membrane distal CRD contains the preligand binding assembly domain (PLAD), which plays a critical role in ligand-mediated formation of active receptor complexes. Soluble TNF (sTNF) and transmembrane TNF (tmTNF) stimulate signaling via TNFR1 and TNFR2 in different ways. sTNF binds TNFR2 with subnanomolar affinity and it requires tmTNF to secure this binding and thus generate a robust activation [11]. TNF binds to TNFR1 with higher affinity than TNFR2. Without tmTNF, the binding of sTNF to TNFR2 forms a short-lived, signaling-incompetent, and transient complex. The activity of the receptors varies widely. This difference is determined by the intracellular structure of the receptors, with TNFR1 containing the “death domain” (DD); while TNFR2 is characterized as a TNF receptor associated factor (TRAF) with no death domain. The tumor necrosis factor receptor –associated factor 6 (TRAF6) appears to be involved in neuropathic pain. Weng et al., examined murine chronic visceral hypersensitivity in a murine model using TRAF 6 small interfering RNA injected intrathecally. This caused a significant reduction in the amplitude of spontaneous excitatory post-synaptic currents at the dorsal horn level, which is an indicator of reduced neuronal irritability. Genetic  knockdown of TRAF 6 and caused a significant downregulation of cystathionine β synthetase expression- a recognized mediator of pain hypersensitivity. TRAF 6 is a potential therapeutic target in chronic, neuropathic visceral pain, especially in patients with irritable bowel syndrome [12]. The major cellular sources of TNF are macrophages, immune cells, and microglia. TNF expression spikes in response to infections or tissue damage [13, 14]. TNFR1 is expressed on a multitude of effector immune cells and TNF binding to TNFR1 results in the generation of a proinflammatory environment. TNFR2 is found predominantly expressed on activated T cells and plays an important role in the regulation of the immune response. TNF-α is activated by the TNF-α-converting enzyme (TACE). TACE is a protease and a member of the A- disintegrin and metalloproteinase (ADAM) family and is also known as ADAM17. The protease is known to cleave more than 80 different membrane-anchored proteins and factors. These include neurotrophins, TNF-α, TNF receptor, fractalkine, IL-6 receptor, endothelial growth factor receptor (EGF-­ R) ligands [15]. In a murine model of genetic ADAM deficiency, ADAM17ex/ex, animals who were made hypomorphic with respect to ADAM 17 exhibited hyposensitivity to noxious stimulation, elevated mechanical allodynia thresholds, and impaired heat and cold sensitivity. These animals were also found to demonstrate changes in the functional electrical properties of unmyelinated nociceptors, including variations in resting membrane potential, afterhyperpolarization, and firing patterns in specific subpopulations of sensory neurons in ADAM17ex/ex mice. These are all changes consistent with the establishment of activated TNF-α effects [15]. It is here that we focus further upon the role of TNF-α in the transition of acute pain to chronic pain. Acute pain invariably involves a neural insult with subsequent inflammation and a resultant immune response [16]. Direct administration of TNFα

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into the sciatic nerve in a murine model produces a pain hypersensitivity pattern which is similar to that found in humans [17]. TNF binding to TNFR1 results in the generation of the apoptotic cascade with cell injury in addition to the development of mechanical allodynia and thermal hyperalgesia. These findings which were discovered via the employment of murine models which lacked TNFR1 receptors (TNFR1−/− mice) indicate that there is an essential role of TNF in the development of neuropathic pain [18]. TNFR2 appears to play a neuroprotective role [19]. This tracks with the 2019 finding by Fischer et  al., that TNFR2−/− mice demonstrate chronic non-resolving pain following CCI and that in this model, regulatory T cells (Tregs) are also depleted [20, 21]. The search for antibody-based interruption of TNF-α as treatment for neuropathic pain has been exhaustive. Yet several pre-clinical and clinical trials have yielded no efficacious candidates in this therapeutic intervention; [22–27] and a recent systematic review and meta-analysis failed to show superiority over placebo in the treatment of low back pain and sciatica [28]. For this reason this chapter will not belabor the point of speculating about immunotherapy as a mechanistic approach to treating TNFα-mediated neuropathic pain. The remainder of this chapter is divided into two sections. The first will discuss the recognized role of TNFα in the transition of acute to chronic, neuropathic pain. The second section deals with therapeutic interventions that target specific stages in the mechanism of the TNFα-­ mediated injury to chronic pain. The inflammatory reaction is triggered by and incorporates a number of important physiologic pathways. Nitrosative stress, or the excessive production of nitric oxide, and frequently the production of superoxide anions, results in the subsequent generation of peroxynitrite, and the release of inflammatory mediators: IL-1β, TGF-1β, and TNFα; and caspase 3. It has been shown in a murine model that when nitrosative stress is modulated there is reduced release of TNFα and other inflammatory cytokines, and a concomitant decrease in neuropathic pain behavior [29]. Likewise, the oxidative stress generated by hyperglycemia leads to TNF-α over expression in the spinal cord. Interestingly this metabolic derangement results in the reduced production and transport of nerve growth factor with a subsequent nerve damage repair imbalance and the resultant development of neuropathic pain. This oxidative stress initiated injury was elucidated in 2010 when Comelli et al. utilized a diabetic murine model and administered the selective cannabinoid 1 (CB1) receptor inhibitor, rimonabant. This compound effectively reduced oxidative stress by restoring depleted glutathione. In addition, it indirectly inhibited TNF-α over expression in the spinal cord and functionally increased NGF [30]. The pro-inflammatory role the TNF-α played in the development of neuropathic pain was further examined in recent (2020) studies. One study explored the effect of the piperazine derivative antianginal drug, Ranolazine [31, 32] was studied versus the thiazolidinedione class antihyperglycemic drug, pioglitazone [33] in a diabetic murine model. Specifically, the roles of sciatic interleukin (IL)-1B, TNF-α, voltage-­gated sodium channels (Nav 1.7) and peroxisome proliferator activated receptor-­gamma (PPAR-δ) expression were determined in the presence of RN or PIO. The animals were tested for thermal hyperalgesia and mechanical

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allodynia, the sciatic nerve homogenates were examined for levels of TNF-α and IL 1B, and Nav 1.7 channel expression. Both PIO and RN improved neuropathic behavior and significantly reduced TNF-α and IL-1B levels RN showed the highest efficacy, demonstrating its role as a neuroprotective agent via disruption of the IL-1B and TNF-α dependent neuroinflammatory cascade [34]. Further iteration of the inflammatory role of TNF-α in diabetic neuropathic pain was demonstrated in a study of TNF-α and the proinflammatory protein CXCR4. Levels of this protein were measured from the initiation to the 5-week point of streptozotocin induced DM in a murine model, and were correlated with pain behaviors demonstrated by the animals. By 5 weeks of diabetes there was significant upregulation of CXCR4 and TNF-α in the dorsal horn that correlated with pain behavior in the animals [35]. A similar relationship between inducible nitric oxide synthase and TNF-α and neuropathic pain behavior is seen in the inflammatory disease autoimmune neuritis [36]. The theory of neuroimmune disturbance-mediated neuropathic pain was furthered in a study by Bernateek et al., in which they demonstrated the presence of regionally localized (hands) TNF-α in 3 patients in the early stages (Type 1) of complex regional pain syndrome (CRPS). Interestingly this was not found in the late stage of CRPS [37]. The activation of the TNF-α expression pathway in microglia appears to involve long noncoding RNA (1nc RNA). One of the functions of lncRNAs is the regulation of translation. lncRNAs, while rarely translated themselves may both suppress and activated mRNA translation, they function in all aspects of gene expression through a variety of mechanisms of action [38]. (See Chap. “Protein Kinase C and the Chronification of Acute Pain”) The involvement of IncRNAs as they relate to neuropathic pain is seen in the activation of microglia. Li et al. examined 56 IncRNAs and 298 mRNAs and found that differentially activated mRNAs triggered the NF-KappaB signaling pathway; the nucleotide-binding oligomerization domain-like containing protein (NOD) signaling pathway; [39] and the TNF signaling pathway. All of which (see Fig. 1) play critical roles in neuronal sensitization and the development of chronic pain. Thus several lncRNAs may be involved in microglial activation [40–42]. One example of this regulatory function is the long noncoding RNA, Linc 00052. While implicated in the development of multiple diseases, a specific murine model utilizing spinal nerve ligation revealed that Linc 00052 was specifically elevated. Genetic knockdown of Linc 00052 repressed the process of neuro inflammation and both the pro-inflammatory interleukin-6 (IL-6) and TNF-α were inhibited, while the anti-inflammatory IL-10 was induced. They also found that microRNA-448 which plays a crucial role in promoting the pathogenesis and progression of neuropathic pain, by significantly increasing the protein levels of IL-1β, IL-6 and TNF-α through its targeting of sirtuins-1 (SIRT1). SIRT1 downregulates acetylated-nuclear factor kappa β (ac-NF-kB) (see Fig. 1) [40]. The group concluded that Linc00052 could be targeted as a potential therapeutic intervention in the treatment of neuropathic pain [43]. Another long non-coding RNA, Linc00657, was found to be greatly increased in a chronic constriction injury murine modeling and its inhibition suppressed neuropathic pain via the alleviation of mechanical and thermal hyperalgesia [44].

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Tryptophan

© G. Hint z 2020

Na+ pH 8

pH 4

Fig. 1  The three-step interaction by which TNFα inserts into a cell membrane hydrocarbon core of the phospholipid bilayer where it forms its own ion channel following neural injury. The image also depicts the inverse relationship of the insertion to pH

In 2020, Duan et al. examined miR-155 in relation to treatment of bortezomib-­ related chemotherapy induced peripheral neuropathy. Specifically, they explored miR-155 and the expression of TNFR1 the murine spinal cord horn. Inhibition of miR-155 attenuated mechanical allodynia and thermal hyperalgesia and correlated with decreased expression of TNFR1, p38-MAPK, TNK, and TRPA1, miRNA analogues were found to amplify the TNFR1-TRPA pathway and increase neuropathic pain. They concluded that miR-155 was an attractive target for the treatment of neuropathic pain [45]. The miR-133a-3p micro RNA was examined via transfection into murine Schwann cells using a recombinant adeno-associated virus type 8 (rAAV8) vector. In both diabetic and normal rats, AAV-miR-1332-3p induced mechanical allodynia and phosphorylated-p38 MAPK activation. Inhibitory, synthetic microRNA to miR-­133a-3p administration alleviated diabetic neuropathic behavior while overexpression of miR-133a-3p in the sciatic nerve increased pain [46]. Their work identified miR-133a-3p as a therapeutic target for the treatment of diabetic neuropathic pain [47]. [It must be iterated that miRNAs can both suppress and activate translation of miR-134-5p. In contrast, miR-133a-3p (above), has been show to strongly alleviate neuropathic pain when it is overexpressed via specific suppression of several inflammatory cytokines including IL-6, IL-1β and TNF-α. The nexus of this mechanism appeared to be the twist 1 gene and its inhibition of NF-Kappaβ translation, (see Fig. 1) [46, 48]. The authors logically suggested that miR-134-5p and its

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regulation deserve study as potential therapeutic target in the treatment of neuropathic pain. The microRNA, miR-340-5p falls into the anti-inflammatory and thus the anti-­ algogenic subset of this group. It was suggested as a therapeutic focus as a result of its likely inhibitory effect on the repressor activator protein 1 (Rap1). Rap1 is known to function via NFKB activation [49] (Fig. 1) in pro-inflammatory macrophages and thus promote a pro-inflammatory environment [50]. The downregulation of TNF-α synthesis is accomplished by the signal transducer and activator of transcription (STAT3) which is activated by prototypic anti-­ inflammatory cytokine IL-10 [49]. The IL10-STAT3 interaction is critical to the inhibition of cascade of inflammation initiated by LPS [51]. The long non-coding RNAs, linc00311 and IncRNA-AK141205 inactivate STAT3 and thus allow unopposed of LPS-mediated expression of cytokines. Indeed, downregulation of lin00311 and lncRNA-AK141205 by specific siRNAs attenuate mechanical allodynia. Thus methods of silencing 9ncRNA-AK141205 and for linc00311; or the upregulation of STAT3 deserve exploration as potential therapeutic options in the treatment of neuropathic [52]. The lncRNA small nucleolar RNA host gene 4 (SNHG4) is upregulated in the SNI model of murine neural injury. When SNHG4 was genetically removed neuropathic pain was attenuated. In addition, this same genetic modification inhibited IL-6, IL-12 and TNF-α all while inducing IL-10. SNHG4 targets and inhibits the function of miR-423-5p and its loss contributes to neuropathic pain progression via the increase in IL-6, IL-12 and TNF-α mRNA expression. The exact step in the TNF-α generating cascade have yet to be described [53]. Activation of the MAPK signally pathway is the mechanism by which miR-101 promotes hypersensitivity and the inflammatory response of microglial cells. Qiu et al. used a CCI, murine model and conducted miR-101 and MKP1 gain-and-loss of function experiments. Their work revealed that miR-101 was highly expressed in the spinal dorsal horn and microglia of CCI rat models. Overexpression of miR-101 increased IL-1β, IL-C and TNF-α. They demonstrated that miR-101 inhibited MKP-1 expression and promoted the expression of MAPK, as mentioned above, thus activating the MAPK signaling pathway and promoting the generation of TNF-α [54]. While the IL10-STAT3 pathway has an anti-inflammatory effect, in other settings STAT may be pro-inflammatory. A 2017 study of oxaliplatin-induced chronic painful neuropathy showed that the cytokine receptor CXCL12 was upregulated in the dorsal root ganglion. The inhibition of STAT3 with S3I-201which preferentially inhibits STAT3 DNA-binding activity and diminishes STAT3 tyrosine phosphorylation [55] prevented the upregulation of CXCL-12 expression in the DRG and thus prevented chronic pain related to oxaliplatin [56]. This illustrates the distinct difference between TNF-α/IL-1β-dependent STAT3 and IL10/STAT3. Yang et al., studied interleukin 6 m the murine red nucleus and found that it demonstrated close correlations with the upregulation of TNF-α and IL 1β. Antagonism of either TAK2 with AG490 or ERK with PD 98059 in the red nucleus of rats with SNI

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inhibits the up-regulation of IL-1β and TNF-α and markedly diminished neuropathic pain behavior. Pretreatment with PD98059 did not. This same pretreatment did inhibit the upregulation of TNF-α. They concluded that IL-6 induces the expression of TNF-α through the JAK2/STAT3 pathway [57]. This emphasizes the striking difference between the anti-inflammatory effect of the IL10/STAT3 relationship, and the proinflammatory pro-algesic effect of the JAK2/STAT3 relationship. The role of TNF-α in the subjective and emotional experience of neuropathic pain was studied with essays of c-Fos, a recognized marker of neuronal activity. The murine anterior cingulate cortex was studied in the setting of spared nerve injury. Microinjection  of anti-TNF-α antibody in to the ACC completely eliminated c-Fos overexpression, greatly attenuated pain aversion behavior and mechanical allodynia as measured by ipsilateral pain withdrawal studied between injury days 0–14. This group also employed chemo genetic tools to modulate the neuronal function in the ACC [58].

 esigner Receptor Exclusively Activated by Designer D Drugs (DREADD) Designer Receptor Exclusively Activated by Designer Drugs (DREADD) of the muscarinic receptor class, specifically M4 Gi-coupled human, and m3 Gg coupled human [59, 60] were used to manipulate TNF-α levels in the ACC and the mechanical paw withdrawals threshold. Positive interactions between TNF-α and ACC neurons might modulate the cytokine environment, which in turn could contribute to the neuropathic pain response [58]. This interaction has helped indict another mechanism of TNF-α- mediated pain chronification.

T-Box Transcription Factor TBX3 is a member of the T-box transcription factor gene family and it is critical to the development of the heart, limbs and mammary glands. It is also a strong inhibitor of certain tumor suppressor genes. Fibroblast growth factor receptors (FGFRs) are members of tyrosinase kinase (TrK) transmembrane receptors family. FGFR3 expression increases in the spinal dorsal horn following partial sciatic nerve ligature. This upregulation results, in turn in the upregulation of glial fibrillary acidic protein, a marker of glial activation, and the result increase in TNFα-mRNA expression. A correlation between was TBX3 and FGF signaling was found in cultured spinal astrocytoma; with a TBX3 protein expression decrease in response to FGFR3 and FGFR3-TBx3 activation and TNFα knockdown in astrocytes; This lead to the conclusion that FGFR3-TBX3 axis participated in astrocyte activator, and maintenance of NPP via TNF-α synthesis in the spinal dorsal horn [61]. The group concluded speculated that this is a viable molecular therapeutic target for the treatment of NPP.

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Purinergic Receptor System TNF-α also appears to work with the purinergic receptor system. These receptors are examined in some detail elsewhere in this textbook, but for the purpose of this discussion it is important to note that there are seven purinergic (P2X) receptors subtyped. The P2X4 receptor is distributed among neurons, astrocytes, and microglia. The receptor serves to modulate cellular excitability, transmission and, therefore, plays an important role in the development of neuropathic pain. In a 2019 study Su et al. examined P2X4 function in Schwann cells in a murine model following nerve crush injury. They utilized genetic manipulation to overexpress P2X4R in Schwann cells. This overexpression of P2X4R and the subsequent agonism of the receptor promotes motor and sensory functional recovery and accelerates nerve remyelination, P2X4R is localized in Schwann cell liposomes in the peripheral nervous systems where, in cell cultures, TNF-α both upregulates P2X4R synthesis and enhances trafficking of the expressed receptor to the Schwann cell surface. Interestingly TNF-α contributes to accelerated nerve remyelination via a P2X4R dependent increase in brain neurotrophic factors (BDNF); the study iterates the potentially beneficial effect of TNF-α in a normal neural injury setting [62].

Kinin Receptor System The role of bradykinin (BK) in the development and maintenance of neuropathic pain has been well-described, [63] and the association of TNF-α and kinins has been examined in animal models of neuropathic pain behavior. A study by Quintao et al., in 2019 sought to characterize the interaction of kinin receptors and TNFR1/p55 in TNF induced mechanical hypersensitivity in a murine model. Employing TNF/p55 intraneural, brachial plexus injection, this group found that neuropathic pain behavior, specifically the mechanical paw withdrawal threshold reduction, was increased significantly. They then determined the connection between TNF1/p55 and B1 and B2 kinin receptors using knockout mice and mRNA quantification in the target nerve. They determined that the connection between TNF and the kinin system suggested the relevance of B1R and B2R in the process of neural sensitization [64]. Patients with diabetic neuropathy have been shown to have elevated serum levels of TNF-α. In the streptozotocin-induced diabetic murine model it has been shown that TNF-α causes an increase in the expression of NaV1.7. When murine DRG neurons are exposed to TNF-α for 6 hours, the animals develop hyperalgesia. De Macedo et al., found the logically predicted increase in total current density derived from both tetrodotoxin sensitive (TTXs) and resistant (TTXr) channels; and a steady state shift in the activation and inactivation curves of the total and TTXs sodium currents. Thus TNF-α was show to sensitize DRG neurons at least in part via a whole cell sodium current-dependent mechanism [65].

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TNFα-Targeting Therapeutics Genetic Manipulations  ranslational Manipulation of the Hyperpolarization-Activated T Cyclic Nucleotide-Gated (HCN) Channel Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated ion channel superfamily. The gating of these is mediated by both hyperpolarization of the cellular membrane as well as by cyclic nucleotides. HCN channels produce hyperpolarization currents (Ih) which play an important role in spontaneously firing cardiac pacemaker activity, and as controllers of neuronal excitability. They can cause cardiac dysrhythmias, ataxia, epilepsy and a number of pain disorders, including neuropathic pain when they malfunction [66]. Ivabradine is a member of the class of drugs known as hyperpolarization-activated cyclic nucleotide-gated (ITEN) channel blockers. It is approved by the FDA in the US for use in patients with stable heart failure and an ejection fraction of 35% or less. In the realm of neuropathic pain, it was hypothesized that ivabradine could directly influence inflammatory responses. Miyake et  al. studied the effect of ivabradine on inflammatory pain in a carrageenan hindpaw injection murine model. Subcutaneous ivabradine injection increased the pain threshold, inhibited the carrageenan-induced accumulation of leukocytes and decreased TNF-α expression. In addition, ivabradine inhibited LPS-stimulated production of TNFalpha incubated in vitro. While the authors concluded that locally injected ivabradine was effective against inflammatory pain via HCN channels, the exact mechanism of this anti-inflammatory effect was not specifically described. In another HCN study that same year it was found that the role of increased HCN2 channel expression likely contributed to mechanical allodynia and thermal hyperalgesia; the activation of astrocytes, microglia and NF-KB in mice with SNI. Intrathecal injection of the HCN2 blocker ZD-7288 and siRNA for ITEN2 led to a reversal of neuropathic pain behavior and a significant decrease in MCP-1, IL-1β and TNF-α [67].  enetic Suppression of Poly – (ADP-Ribose) Polymerase G (PARP-1) Inhibitors PARP-1 is a transcriptional coregulator that detects DNA damage and directs repair of genetic material. It is the chief human PARP enzyme involved in the DNA damage response. The nerve injury murine model (SNL) results in a significant increase in the expression and activation PARP-1 in the ipsilateral DRG and spinal dorsal horn. Inhibition of PARP-1 by PJ-34 or Tiq-A caused reduction in neuropathic pain behavior. Expression of PARP-1 could also be directly suppressed by PARP-1 siRNA which resulted in the alleviation of TNF-α protein NS suppression seen with PJ-34 and Tiq-A administration. Thus PARP-1 manipulation may also present a promising avenue for treating neuropathic pain [68].

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 anoparticulate Genetic Manipulation of TNF-α N Neuronal control over microglia in the normal, non-injury state is critical to the prevention of potentially injurious initiation of immunochemical cascades when these functions are not absolutely necessary. It follows that these mechanisms may prove more or at least equally harmful if they continue to function unchecked after a chemical or biologic threat has been and successfully overcome. When this over response does occur, neuronal injury, destruction, or the development of neuropathic pain result. The fork head box protein P3 is an important regulator of CV4+ regulatory (Treg cells) gene function. It suppresses the activation and function of other leukocytes secretes anti-inflammatory cytokines, and expresses co-­inhibitory molecules. FOXP3 expression is important for the continuation of modulation. Full  length FOXP3 suppresses gene expression mediated by NF-KB and other proteins [69]. In a 2019 study, Shin et  al., demonstrated that FOXP3, introduced via nanoparticles (Fox p3 NPs) suppressed microglial cell activity and down-­regulated pro-nociceptive genes, while upregulating anti-nociceptive genes in the spinal dorsal horn [70]. We find this to be a most exciting concept for the potential treatment of neuropathic pain. Clearly more research needs to be performed in this discipline [70]. Another nanoparticle-related study in 2019, employed clustered regularly inter spaced short palindromic repeats-associated protein-9 nuclear, (CRISPR/Cas9) to create p38 CRISPR/COS9 PLGA nanoparticles to edit the p38 gene in spinal microglia and subsequently reduce microglial activation. In the murine model of mechanical allodynia, intrathecal injection of p38 Cas9 NPs alleviated neuropathic behavior and significantly decreased the expression of IL-1B, IL-6 and TNF-α [71].  enetically Reduced Responsiveness to TNF-α G The M1 or proinflammatory microglial population may be manipulated by genetic conversion, i.e., creation of an activator chemokine (CCL21) deficient, murine phenotype. These animals exhibit little or no hypersensitivity to mechanical or thermal stimulation in the setting of experimental spinal cord injury (SCI) as compared to wild type animals. This was determined to be the result of reduced M1-induction of TNF-α and IFN-δ in the CCL21 deficient animals. The study suggested that suppression of inflammatory cytokines by decreasing the number of M1-type microglia macrophages at the site of injury is associated with alleviation of neuropathic pain in this model [56].  enetic Manipulation of Annexin 10 G Annexin 10 is a 37 kDa protein that is part of the annexin family. It is induced by glucocorticoids. It contributes to neuropathic pain by activating spinal extracellular regulated kinase (ERK) signaling and subsequent release of TNF-α and IL-1B. It was found to increase neuropathic pain in a murine model of SNL. Knockdown of ANXA-110 at the spinal cord lead suppressed the SNL-induced hyperalgesia and blocked the activation of NF-KB, (Fig. 1) and subsequently TNF-α and IL-1B. This occurred in both the early and late phase of neuropathic pain [72].

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Plant Based TNFα Targeted Therapeutics Naringenin The flavonoid naringenin (NAR) possesses various pharmacological activities. It is an anti-inflammatory and has neuroprotective activities. Zhang et al. investigate the effects of NAR on microglial m1/m2 polarization NAR was found to inhibit LPS-­ induced microglial activation. It also shifted the m1 pro-inflammatory microglial phenotype to the m2 anti-inflammatory state through the decreased MAPK dependent expression of TNF-α IL-1B. This is further evidence of the potential value of flavonoids in treatment of neuroinflammatory-related disorders [73].

Resveratrol Resveratrol is an antioxidant found in red wine, peanut  skins, blueberries, pistachios, cocoa and dark chocolate. Yin et  al. found  that the vital proinflammatory matrix metalloproteinases 9 and 2 (mMP-9 and mMP-2) were suppressed by pretreatment with resveratrol which altered and also delayed CCI-induced mechanical allodynia. Resveratrol also reduced the expression of IL-1β and TNF-α; and diminished neuronal excitoxicity. The authors of this study also postulated that the inhibition of mMP-9/2 activation and pain sensitization may be related to the TLR-4/ NF-KB signaling pathway and that this might which might be negatively regulated by the induction of SOC53. In addition resveratrol was found to be an activator of the protein deacetylase sirtuin 1 gene which mediates (among of the function) anti-­ inflammatory activity [40, 74]. Resveratrol was also found to attenuate 2, 4, 6  – trinitrobenzene sulfonic acid (TNBS) – induced visceral pain hypersensitivity via reduction of spinal TRAFG, pNF-KB, TNF-α and IL-1B [75].

Folashade (Lippia) The Lippia grata plant is the source of an essential oil that has reported anti-­ hyperalgesia effect. It is a tropical to subtropical herbaceous aromatic plant found widely throughout Africa, and South and Central America. The essential oil is used alone or complexed with B-cyclodextrin and has been found to decrease TNF-α and PKA to pre-insult levels.  It inhibits  voltage-gated calcium channels which suggests some consideration as a potential therapeutic agent for neuropathic pain management [76].

Bergapten The organic chemical Bergapten is found in several plants. These include anise, citrus species such as lime and bitter orange; and the apiaceae family which include

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celery, carrot, and parsley. The efficacy of Bergapten in alleviating peripheral neuropathic pain was examined by Singh et al. in 2019. The group compared bergapten with gabapentin in a murine model of vincristine-induced neuropathic pain behaviors. Assays were performed for TNF-α, IL-1B, oxidative stress and expression of iNOS, COX-2 and NF-KB in the spinal cord and in the plasma. The bergapten group reduced neuropathic pain behavior and to also causal the attenuated of TNF-α, IL-1B, oxidative stress and the attenuation of NFKB, COX-2 and iNOS expression [77].

Fumaria Officinalis Fumaria officianalis, also known as Earth smoke, is a poppy the seeds of which have an alkaloid-rich function that contain two major, pharmacologically active alkaloids were incorporated into 96.6I 1.87 nm niosomes in a study by Raafat et al. and administered to animals in an alloxan-induced diabetic murine model of neuropathic pain. The alkaloids were shown to increase in vivo anti-oxidants activity as determined by lipid peroxidation (LPO); catalase (CAT) enzyme activity and the activity of glutathione reductase (GSH). In addition, the alkaloids reduced cytokine levels in general and in particular IL-6 and TNF-α and simultaneously elevated IL-10 levels. This formulation warrants further study [78].

Conjugated Linoleic Acid Conjugated linoleic acid (CLAs) are known to have anticarcinogenic and lipid/ energy metabolism-modulating effects. They are found in several animal products such as milk, red meats, especially beef, with grass-fed beef containing higher levels than grain-feed beef. In addition, CLAs are also found in safflower and sunflower oil. The concentration of CLAs in foodstuff is considered insufficient to provide any significant therapeutic application from these sources alone and recently microbial production of these and other conjugated fatty acids have been explored [79]. Their role in neuropathic pain is less well described. In one 2019 study in a murine model, neuropathic pain was induced with the use of partial sciatic nerve ligation preparation (PSNL). This induction was followed with 4  weeks of CLA treatment. Animals that received CLA had significantly less mechanical and thermal allodynia than animals in the PSNL group alone. Electrophysiologic improvement was also noted in the CLA group as defined by improvement in nerve conduction velocity as well as in gastrocnemius contractile strength. In addition, CLA improved the intrinsic antioxidant state by restoring mitochondrial manganese superoxide dismutase (Mn SOD) to the pre-insult state in PSNL preparation animals. CLA also effectively reduced the levels of interleukin -1B, sciatic myeloperoxidase (MPO) activity, activating transcription factor-3 (ATF-3) activity, and reduced TNF-α expression [80].

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Excoecaria Agallocha Excoecaria agallocha, also known as milky mangrove or blind-your-eye mangrove, is native inhabitant of shorelines and estuaries in the tropical and subtropical coastal regions of the world. The milky latex discharged from the bark of this tree may cause temporary blindness and skin blistering. The latex is also known to be biocidal to certain marine species and phytoplankton [81]. In 2019 Sharma et al. investigated the use of various extracts of E agallocha in the treatment of complications of diabetes and specifically diabetic neuropathy. They used a streptozotocin-induced diabetic murine model and administered oral doses of e agallocha extract. Among the beneficial effects of this therapy included weight loss, improved renal function, and better blood sugar levels. They also found that the extract reversed hyperglycemic-­ based oxidative stress and decreased serum and tissue levels of nitrite, TGF-β, IL-1β and TNF-α. The study raises the question of any applicability that these extracts may have in the clinical setting [82].

Aegle Marmelos The hydroalcoholic extract of the flavonoid, aegle marmelos bark has been shown to be of use in neuropathic pain. It is found typically in Asia and Southeast Asia and is also; known as bael fruit, golden apple, stone apple, and Bengal quince. The extract was studied in the setting of vincristine-induced peripheral neuropathy and was found to reduce the pro-inflammatory mediators TNF-α, IL-1β and IL-6 [83].

Tribulus Terrestris The annual plant tribulus terrestris (TT) is indigenous to Southern Eurasia and Africa. Saponins extracted from this plant are capable of attenuating vincristine-­induced neuropathic pain in a murine model. In addition, TT saponin therapy attenuated TNF-α, IL1β and IL-6 levels, which gave evidence for its anti-inflammatory effect [84].

Bisabolol The chamomile-derived bisabolol is a natural monocyclic sesquiterpene alcohol that has been studied for its potential antinociceptive and anti-inflammatory effect. Fontinelle et al., studied this agent alone and in combination with cyclodextrin in a murine model of neuropathic pain. BIS and BIS-βCD inhibited TNF-α production and, further, stimulated the release of IL-10 in the spinal. The group logically postulated that BIS should be subjected to further study and ultimately examined in a clinical setting [85].

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Benfotiamine The vitamin B1 derivative, benfotiamine was studied in a murine model of neuropathic pain in combination with and apart from ketamine in a LPS stimulated neuronal culture. Both ketamine and benfotiamine suppress the immune response (combatting intracellular parasites and perpetuating autoimmune diseases), [86] via the inhibitor of TNF-α production and secretion [87].

Levo-Corydalmine (I-CDL) (Berberine) Levo-corydalmine is a tetra hydro-protoberberine which inhibit the expression of phosphorylated apoptosis signal regulating kinase (p-ASK-1) an enzyme thought to be related to the activation of spinal microglia in the neuropathic pain murine. Perhaps I-CDL inhibited translocation of NF-KB and upregulation of p-p65, TNF-­ α, and IL-1B [88]. This is related to the compound berberine, which exerts its neuroprotective effect in murine diabetic neuropathy pain models via modulation of pro inflammatory cytokines IL-1B, IL-6, and TNF-α. In addition, berberine reduces oxidative stress BDNF, IGF-1, PPAR-γ and AMPK expression which ameliorate allodynia, and hyperalgesia in the murine model [89]. This reduction of TNF-α, IL-6, IL-10 as well as i-NOS and COX-2 reinforced the potential analgesic value of berberine in works by Liu that same year [90].

Cannabinoids Studies by Zhou et al. in 2019, and Kumawat et al. 2019 point to agonism of the cannabinoid of the cannabinoid 2 receptors and the decrease in pro-inflammatory cytokines and pro-apoptotic factors. Specifically, the CB2 receptor activation leads to the reduction of TNF-α, IL-6, NK-K B; and the amelioration of ROS and RNS, which play a role in apoptosis. The use of cannabinoids as an analgesic in several pain syndrome is now common and well described [91, 92].

Withania Somnifera Withania somnifera, also known as Indian ginseng, poison gooseberry, or winter cherry is another plant known for its anti-stress activity contains the active ingredient, compound X [93]. In a murine model of neuropathic pain. W. somnifera extract also resulted in improvement in all pain-related symptoms and animals treated with extract showed improvement in production of superoxide ions, myeloperoxidase and TNF-α. The authors believed that those effects were the result of anti-oxidant properties, and thus should be studied as a prospective anti-neuropathic pain therapy [94].

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B Vitamins The B vitamins, thiamine, nicotinamide and riboflavin have been shown to exhibit antinociceptive properties in murine models of paclitaxel-induced neuropathic pain. In 2020, Braga et  al. used the chemotherapeutic agents to create a long-lasting mechanical allodynia. They were able to attenuate the neuropathic pain behavior by administrating two doses of thiamine nicotinamide or riboflavin on the seventh day following administration of paclitaxel. Interestingly the mu opioid receptor naltrexone attenuated the antinociceptive effect of thiamine. The group observed that all three B vitamin led to reduced expression of TNF-α and CXCL and this was thought to be the basis of the antinociceptive effect. The specific inhibitor step was not described [95].

Loganin The iridoid monoterpenoid, loganin is a well-known herbal medicine which has glucose-­lowering and neuroprotective activity [96]. It prevents certain types of neuronal injury by inhibiting the production of pro-inflammatory cytokines, TNF-α, IL-1B; inflammatory proteins, (including pNFKB and iNOS); receptors TNFR1, IL-1R; and the adaptor protein (TRAF2) of TNF-α. The reduction in NF-KB explains the down regulatory effect on TNF-α and the resultant anti-­ neuroinflammatory effect [96, 97].

Limonene (LIM) Limonene (LIM) is the major component in the oil of citrus fruits, peels, juniper, and it is also found in certain strains of cannabis [98]. It and its main-metabolite perillyl alcohol [POH] are capable of both accelerating neural regeneration and alleviating neuropathic pain. LIM and POH were able to decrease TNF-α concentration following nerve crush injury in a murine model, with POH proving more effective early-on in the neuropathic pain development [99].

Miscellaneous TNF-α- Targeting Therapies  ucleotide-Binding and Oligomerization Domain N (NOD)-like Receptors Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are pattern-recognition receptors that are similar in function to toll-like receptors (TLRs). One significant distinction is that TLRs are transmembrane receptors and NLRs are cytoplasmic receptors. Both play critical roles in the innate immune response by recognizing pathogen-associated molecular patterns and damage-associated molecular

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patterns. It is important to note that NOD-2, NOD-1, NLRP2 and NLRP4 appear to play important roles in the inflammatory cell response cascade demonstrating modulating effects upon the receptor interacting-serine/threonine-protein kinase 2 (RIPK2 or RIP2) and TRAF6. Which in turn modulate NF-KB and MAPK, two critical factors in the generation of pro inflammatory cytokines including TNF-α (Fig. 2) [100]. In a 2019 study, Santa-Cecilia et al., demonstrated in detail that following peripheral nerve injury (SNI preparation) in a murine model that NOD2 and RIPK2 specifically mediates the development of neuropathic pain via the production of TNF-α and IL-1β. Moreover, they proposed that defining NOD2 signaling in the development of neuropathic highlight NOD2 as a potential therapeutic target in this syndrome [101].

LPS TLR4

IRAK-M

IkappaB-alpha degradation NF–kappaB

IRAK-1 Degradation

P13K/Akt

MAP kinase Phosphorylation

JNK

TNF–alpha expression

p38

ERK 1/2

Fig. 2  Summary of multiple pathways to TNFα expression. (LPS lipopolysaccharide, TLR4 Toll-­ like Receptor 4, P13K Phosphotidylinositol 3-kinase, PKB Protein Kinase B, IRAK IL-1 Receptor-­ Associated Kinases, ERK Extracellular Signal-Regulated Kinases, p38 Mitogen Activated Protein Kinase, JNK-C Jun N-terminal Kinases, NF-kappaB Nuclear Factor kappa-light-chain enhancer of activated B cells, TNF Tumor Necrosis Factor)

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Exercise Exercise has been shown to decrease IL-1β, IL-6 and TNF-α as well as neuropathic behavior when used in a murine model of streptozotocin-induced diabetes with accompanied diabetic peripheral neuropathy. When an exercise regimen consisting of 10 minutes of motor-driven rodent treadmill running for 4 days/week for swales. A belt speed of 5 meters per minute for 10 minutes was the initial exercise regimen used. This gradually increased to a maximum of 10 meters per minute for 10 minutes. By the third week, neuropathic pain behavior was significantly improved. This was accompanied by decrease in interleukin (IL)-β, IL6 and TNF-α and a concomitant decrease in the respective receptors. For these cytokines. The group concluded that exercise can play a role in improving neuropathic pain in this model [102]. Spirocyclopiper-Azinium The compound LXM-10 (2, 4-dimethyl-9-B-phenylethyl-3-oxo-6, 9-diazaspiro [5.5] undecane chloride) is a spirocyclopiperazinium salt was studied in 2013 by Zhang et al. and determined to exert significant anti-inflammation effects in acute and chronic murine inflammation models. The mechanism of this beneficial effect was determined to be mediated via either the α 7 nicotinic acetylcholine receptor or the M4 muscarinic acetylcholine receptor. Agonism of either of these receptors by the salt resulted in inhibition of the JAK2/STAT3 signaling pathway (Fig. 1) which resulted in reducing the production of the pro-inflammatory cytokines TNF-α and IL-6 [103]. Later, in 2019, this effect was iterated with the compound LXM-15-­ another spirocyclopiperazinium salt. The beneficial effect of LXM-15 could be abolished by the peripheral nAChR antagonist, hexamethonium; or by methyllycaconitene citrate, an α7 nAChR antagonist. The salt was shown to inhibit the phosphorylation of JAK2 and STAT3, and thus to mitigate the expressions of TNF-α and C-fos in murine DRG, again via peripheral α7 nicotinic receptor agonism [104].  ngiotensin II Type 1 Receptor Antagonism A The anti-hypertensive drug losartan works by antagonizing the angiotensin II type 1 receptor (ATIIR). The drug was examined as a possible analgesic in the setting of paclitaxel-induced neuropathic pain in a murine model. The study analyzed neuropathic pain behavior via mechanical thresholds, titers of inflammatory cytokines, and cellular location of AT1R and IL-1B in the DRG. The results revealed that single and multiple injections of losartan decreased the expression levels of IL-1B and TNF-α in the lumbar DRG, which raised the logical question of whether it could be applied to the clinical setting [105]. Gallic Acid Gallic acid is a trihydroxybenzoic acid. It is a cyclooxygenase 2 inhibitor, an antioxidant, an anti-neoplastic agent, a human xenobiotic, an arachidonate 15 lipoxygenase inhibitor and an inhibitor of apoptosis [106]. In 2019, Kaur studied the efficacy of paclitaxel-induced neuropathic pain in a murine model. Gallic acid was found to attenuate neuropathic pain behavior and to reduce thiobarbituric acid reactive substances, total calcium superoxide anion, myeloperoxidase, and TNF-α. The

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group concluded that gallic acid is neuroprotective against paclitaxel-induced neuropathic pain secondary to its anti-oxidant function regulation of intracellular calcium ion concentration and its anti-inflammatory function based in part on its ability to regulate TNF-α expression [107].

Remifentanil The short-activing mu opioid receptor agonist narcotic analgesic remifentanil was studied in combination with the mixed agonist-antagonist opioid analgesic, dezocine, with relation to perioperative signs, serum TNF-α, and IL-6  in liver cancer patients undergoing radiofrequency ablation, (RFA). The group compared this pairing against midazolam-remifentanil intravenous anesthesia. Besides providing a significantly analgesic effect and shorter wake-up times, the dezocine-remifentanil combination was found to decrease the expression of TNF-α to a greater extent than dezocine-remifentanil [108]. In another remifentanil study, a murine model was used to evaluate thermal and mechanical hyperalgesia in the paradoxical remifentanil-induced hyperalgesia environment. Von Frey tests and hot plate tests were employed along with measurement of protein expressions of TRPV1, protein kinase C, mRNA level of Trpv1, TrpaI1, Trpv4 and Trpm8. In addition, the group assessed TNF-α, IL-1B and IL-6 levels in the spinal cord. The remifentanil infusion, as predicted, induced thermal hyperalgesia and mechanical allodynia, accompanied by increased TRPV1 and PKC titers in the DRG. Remifentanil also increased TNF-α, IL-1β and IL-6 levels in the spinal cord; and activated astrocytes at the same site. The group concluded that remifentanil hyperalgesia includes a dominant TRPV1-PKC signaling pathway. Yet we find further ramifications that support the potential study of the several agents described to mediate TNF-α earlier in this chapter, these may actually provide viable means for treating this complication of specific narcotic analgesic therapy [109]. Thetanix® The accepted maintenance therapeutic product for treatment of Crohn’s disease, Thetanix® has a unique mechanism of action in that it antagonizes transcription factor NFKB and this reduces the inflammatory cytokines TNF-α and IL. In a study by Hansen et al. in 2019 the safety and tolerability of Thetanix was established in the pediatric patient population. A logical sequel at this point would be a trial of this drug in other settings of neuropathic pain [110]. Oxytocin Other pharmacologic agents not usually associated with anti-inflammation analgesic have been found to yield anti-cytokine effects. For instance, in the setting of bone cancer pain, while it is not clearly understood TLR4 is suspected of playing an important role in the evolution of this syndrome. The hypothalamically produced and posterior pituitary gland-released peptide hormone, oxytocin in a murine model of bone cancer pain, suppressed the  up-regulation of TLR4 as well as the pro-­ inflammatory cytokines TNF-α and IL-1β  following intrathecal injection. Pain behavior was assessed via testing for mechanical allodynia and thermal

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hyperalgesia. The behavior improved significantly following the administration of oxytocin. These data indicated that more studies are warranted to better understand this analgesic effect in a clinical setting [111]. The completion of this work would be a bit less daunting, given the pre-existing FDA approval of this drug for clinical use and extant, wide spread use currently.

Hyperbaric Oxygen Hyberbaric oxygen, (HBO) pre-conditioning in a murine model was found to protect against cisplatin-induced neuropathic pain [112]. The angiotensin II receptor type 1 (AT1R) blocker losartan was found to reverse the overexpression of C-C motif chemokine ligand 2(CCL2), TNF-α and IL-6 in a macrophage rich DRG environment. In addition, losartan induced expression of pro-resolving markers (Arginase 1 and IL-10) which indicated a shift in macrophage polarization. In addition, losartan also showed activity as a partial peroxisome proliferator-activated receptor 8 agonist which suggested its possible role as a partial regulator of tumorigenesis [113]. This was also observed, later, with the use of the specific PPAR-8 agonist, pioglitazone [34]. Paeoniflorin ASK-Inhibitor Another effective ASK1 inhibitor, paeoniflorin deserves mention as it shows promise in the CCI murine model. The drug decreases the expression of IL-1b and TNF-α and down-regulates CGRP expression in the injury setting [114].

Modafinil The novel waking drug Modafinil (Modafinil (2-[diphenylmethyl) sulfinyl] acetamide) is a synthetic central nervous system stimulant that is believed to function via dopamine reuptake inhibition. It has also been demonstrated to have some efficacy in the treatment of vincristine-induced neuropathy in a murine model. Following neuropathy induction via intraperitoneal injections of vincristine, there was the expected elevation in TNF-α and IL-1β. Pretreatment with Modafinil reduced TRPA-1, IL-1β and TNF-α levels and also improved behavioral oral, electrophysiologic, and pathological disturbance. It has also been shown to add to the neuroprotective effect of gabapentin. To date, no  clinical studies have been conducted using Modafinil, yet these seem to be warranted at this juncture [115].

Microglial Manipulation Cytokine – Signaling Protein 3 (SOC 53) in Microglia Another study employing a murine model examined the effect of lidocaine on suppresser of cytokine signaling protein 3 (SOCs3) in microglia in the CCI setting. Lidocaine reduced CCI-evoked spinal injury and cell apoptosis. Lidocaine also

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upregulated SOCs3 expression dependent upon pCREB. SOCSS3 overexpression decreased the expression of p38 MAPK and NF-KB stimulated by LPS (See Fig. 1) in addition to several cytokines including TNF-α. Thus the value of lidocaine and SOCs3 combination in neuropathic pain treatment has been suggested and should be pursued [116].

Acupuncture/Acupressure Acupuncture-related, TNF-α downregulation has been found in three recent (2019) studies. In the first two, (Zhao, 2019; Liu 2019) murine models were employed and nociceptive pain was created via CCI.  Therapeutic use of electroacupuncture was examined. In the Zhao paper, electro acupuncture reduced the activation of microglia and downregulated the levels of TNF-α and IL-6 [117]. In both papers, PI3K/AKT was found to be suppressed which inhibited microglial activation [117, 118]. When auricular point pressure was combined with electro acupuncture in a clinical pediatric trial of post herniorrhaphy pain it was found that effective, significant improvement in postoperative pain was attained and that TNF-α, IL-6 and IL-8 serum levels were decreased on post-operatic days 1–3 [119].

Pulsed Radiofrequency Another non-conventional method of manipulating TNF-α and other cytokines in the neuropathic setting includes pulsed radiofrequency (PRF). In a murine model study conducted by Jiang et al., chronic constrictive injury (CCI) was used to acute a neuropathic pain environment. PRF was then applied to either the ipsilateral DRG or sciatic nerve (SN). Pain behavioral tests were conducted pre and post CCI induction of neuropathic pain; after which neural tissues was essayed. The group found that PRF to either the DRG or SN significantly improved neuropathic pain behavior. Both applications were also found to reduce the CCI induced incase in IL-1B and TNF-α, however DRG application had a greater effect [120].

Pentoxifylline The methylxanthine deviated Pentoxifylline is known to have a variety of anti-­ inflammatory effects. Zhao et  al. studied the mechanism of observed analgesic effect of pentoxifylline in bone cancer pain, with respect to TNF-α, IL-6 and TRPA1  in a murine model. Their findings were consistent with earlier work that TNF-α, IL-6R and TRPA1 were upregulated in bone cancer rats; but inhibition of TNFR-1 and IL-6R alleviated mechanical and thermal hyperalgesic [121]. [Zhao, 2019, regulating bone cancer pain]. This was also demonstration in the setting of oxaliplatin chemotherapy – induced neuropathic pain [122].

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Oxyntomodulin Oxyntomodulin is a peptide hormone that is released from the gut postprandially [123, 124]. It is known to bind to the glucagon receptor (GCGR) and the glucagon-­ like peptide-1 receptor (GLPIR). In the TNF-α intrathecal injection murine neuropathic pain model, oxyntomodulin was observed to attenuate TNF-α-induced neuropathic pain and to decrease the release of glial cytokines IL-6 an IL1B through inhibition of the activation of the NF-KB pathway [124].

Thalidomide Thalidomide was studied by Xu et al. in 2019 in a SNL, murine model and found significantly alleviate SNL-produced neuropathic pain. The analgesic mechanism is thought to result from the inhibition of astrocyte and microglia activation as well as down-regulation of TNF-α levels in the spinal dorsal horn [125].

Venflaxine The selective serotonin re-uptake inhibitor, venflaxine is typically used to treat depression, anxiety, panic attacks and social anxiety disorder, however in a study by Taring et  al., its potential value as an analgesic was explored. The group presents a case report in which a patient was administered venflaxine based upon a paper that described elevated TNF-α in the CSF of patients with newly diagnosed persistent headache. The administered venlafaxine based upon the knowledge that the dry binds the 5-HT2A receptor and inhibits TNF-α signaling. The group administered the drug to a patent who had suffered with headache for over 6 years and who had failed to respond to over different medical treatments. Interestingly this patient enjoyed drastic improvement and eventual complete resolution of symptoms with venlafaxine. No further administrations have been reported in the management of intractable headache, but this result is encouraging and we believe that in the appropriate pre-existing physiology setting clinical venlafaxine headache trials are warranted [126].

Summary The role of TNF-α in the chronification of acute encompasses a number of mechanisms. It is expressed following a neuronal injury and can form its own ion channel in a three step interaction with a channel insertion rate in to the neuronal membrane that is inversely proportional to the pH of the cellular environment. The major cellular sources of TNF-α are macrophages, immune cells and microglia and its expression results in a proinflammatory environment following its binding to the TNFR. The TNFR1 receptor, is expressed on a multitude of effector immune cells and TNF binding to TNFR1 results in the generation of a proinflammatory

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environment. TNFR2 is found predominantly expressed on activated T cells and plays an important role in the regulation of the immune response. TNF-α induces oligodendrocyte necrosis, myelin dilatation and periaxonal swelling. It can also cause central sensitization by virtue of its retrograde transport from the periphery to the DRG where a transient rise in TNFR1 occurs. Retrograde transport of TNF-α is inhibited by bupivacaine, tetrodotoxin, and colchicine. The classic, mechanistic sequence that leads to the injury-induced expression of TNF-α is initiated by stimulation of TLR4. Critical steps in this cascade are the MAPK-mediated phosphorylation of ERK1/2, p38MAPK, JNK, and importantly NF-kappaB. It should be remembered that NGF is an upregulating factor for TNF-α. TNF-α synthesis is matrix metalloproteinase-dependent and two independent species of TNF, sTNF and tmTNF are generated. The binding of sTNF to TNFR is short-lived, signaling incompetent, and transient in the absence of tmTNF. The activation of the TNF-α expression pathway in microglia appears to involve lncRNA and mRNA with differentially activated lncRNA-mediated gene expression and mRNA triggering of the NF-kappaB signaling pathway, the NOD signaling pathway and the TNF signaling pathway. All of which play critical roles in neuronal sensitization via microglial activation and the development of chronic pain. A number of potential mechanisms of TNF-α-mediated transitions to chronic pain exist and warrant further experimental examination. These include the involvement of TNF-α in the purinergic receptor system; in the kinin receptor system and in the TTX receptor system. It should be noted that regulation of microglial activation appears to be an attractive therapeutic goal and may hold a critical key to the successful treatment of neuropathic pain. Regarding potential TNF-α targeting therapeutic interventions, there are no conventional treatment options that currently exist as such. We have thus arbitrarily chosen to divide them into plant-derived options (See Table 1), genetic manipulative options (See Table  2); and miscellaneous treatments. These are Table 1  Summary list of plant-based Therapeutics which target TNF-α Naringenin [73] Resveratrol [74, 75] Folashade (Lippia) [76] Bergapten [77] Fumaria Officinalis [78] Conjugated linoleic acid [79, 80] Excoecaria agallocha [81, 82] Aegle Marmelos [83] Tribulus Terrestris [84] Bisabolol [85] Benfotiamine [86, 87] Levo-Corydalmine (I-CDL) (Berberine) [88–90] Cannabinoids [91, 92] Withania somnifera [94] B Vitamins [95] Loganin [96, 97] Limonene (LIM) [99]

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Table 2  List of Genetic Manipulations Targeting TNF-α Translational manipulation of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel [66, 67] Genetic Suppression of Poly – (ADP-ribose) Polymerase (PARP-1) Inhibitors [68] Nanoparticulate genetic manipulation of TNF-α [69–71] Genetically reduced responsiveness to TNF-α [56]

presented with the implicit understanding that each of these must yet be subjected to rigorous basic as well as clinical research in order to confirm or reject what is speculated upon here via plant derived therapeutics, e.g. naringenin; as well as via genetic manipulations.

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Tetrodotoxin and Neuropathic Pain Jimmy Liu and Daryl I. Smith

Introduction Pain is a significant and pervasive public health challenge that interferes with patient quality of life. Neuropathic pain is the result of direct nerve damage or inappropriate action potential propagation. The syndrome is difficult to treat largely due to lack of effective, target-based therapies that have acceptable side effects over the long-term. In a multimodal general health survey conducted in the United States, 64% of respondents reported pain with 15.7% having a probable neuropathic component to their pain [1]. The most common therapeutic interventions employed in the treatment of neuropathic pain involve the use of anti-inflammatories, opioids, and anti-­ epileptics. Anti-inflammatories and opioids are often an ineffective means of treating neuropathic pain due to lack of specific targeting of voltage-gated sodium channels. Anti-epileptics, specifically gabapentin and pregabalin, have been shown to have the most efficacy but only for a minority of patients with specific subtypes of neuropathic pain such as diabetic neuropathy, trigeminal neuralgia, or post-­ herpetic neuralgia [2]. There is a current need for more effective analgesics targeted towards treatment of neuropathic pain. Neurotoxins, by definition, are harmful and often lethal. Modern medicine has a long history of borrowing and adapting the designs of nature. For example, curare is a paralyzing plant-extract whose derivatives have become the basis of several modern muscle relaxants. Botulin is another neurotoxin whose uses are both medicinal (treatment of muscle spasms and migraines), and cosmetic [3, 4]. Digoxin is a J. Liu University of Rochester, Rochester, NY, USA e-mail: [email protected] D. I. Smith (*) University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_4

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medication used in atrial fibrillation and heart failure, and is derived from the Foxglove plant. The angiotensin converting enzyme (ACE) inhibitors were initially developed from studies on snake venom [4]. It appears prudent to explore the available options regarding NaV channel blockers found naturally as they could serve as the basis of new therapeutic drugs. Voltage-gated sodium (NaV) channels initiate and propagate action potentials in excitable cells and are frequently dysregulated or mutated in human disease. Tetrodotoxin is a neurotoxin found most notably in pufferfish, but is also present in other marine animals including mollusks and crustaceans (Fig. 1) [5]. TTX has been the most studied NaV channel-blocking neurotoxin due to its NaV channel subtype selectivity. Another favorable characteristic of TTX is that it does not cross the blood-brain barrier [6]. Worrisome reactions such as seizures and central nervous system depression, side effects that are currently a concern of local anesthetics, could be avoided.

Mechanism of Action Nav channels have been implicated in the transmission of pain within the nervous system [7]. These channels contain active gating mechanisms, display ion selectivity, and are subject to modulation by specific pharmacologic agents. These agents, most notably, are local anesthetics and neurotoxins. Voltage-gated ion channels contain six transmembrane segments (S1-S6) as the fundamental structural unit. Four groups of the six membrane segments [4x(S1-S6)] are linked into a single polypeptide which allows for functional specialization of the homologous but non identical S1-S6 domains (Fig. 2) [8]. A single Nav subunit (a six transmembrane segment) consists of four different structural regions: a voltage-sensor domain (VSD, S1-S4); a pore domain (PD, S5-S6); a selectivity filter which exists between the P1 and P2 pore helices; and a linking segment (S4-S5) [9] (Fig.  3). The P2 helix lines an electronegative Fig. 1  Tetrodotoxin The molecule binds at the selectivity filter at micromolar or nanomolar concentrations which determines the characterization as tetrodotoxin “resistant” or “sensitive”, respectively

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IV.

Na+

III.

II.

Carboxy terminus

I. H

Hydorphobic motif IFMT

+ –)

pore

0

amino acids (+

1 2 3 4 5 N-linked glycosylation

6

+

Amino terminus

Fig. 2  A 3D view of sodium channels. Circles: Amino Acids important for ion conductance and selectivity Circled ‘h’ (Yellow): Hydrophobic motif IPMT (isoleucine, phenylalanine, methionine, threonine) in the inactivation gate. These motifs are thought  to fold into and block the ion-­ conducting pore. (Adapted from Catterall, et al. [8])

extracellular vestibule that attracts cations towards the pore. Both blocking ions and neurotoxins, e.g., tetrodotoxin, bind at the extracellular mouth of the selectivity filter [10, 11]. Here they may prevent nociceptive impulse propagation as well as neural conduction overall. There are nine subtypes of voltage-gated sodium channels. Mutations in the nine Nav channel isoforms differentially expressed throughout the human body are associated with migraine (Nav1.1), epilepsy (Nav1.1–1.3, Nav1.6), pain (Nav1.7–1.9), cardiac arrhythmias (Nav1.5), and muscle paralysis syndromes (Nav1.4) They have been further subclassified as either tetrodotoxin-sensitive (TTX-S) or tetrodotoxin-­ resistant (TTX-R) based on whether they are inhibited at nanomolar concentrations or micromolar concentration of tetrodotoxin (TTX), respectively. The TTX-S Nav channels are Nav 1.1–1.4, 1.6, and 1.7. The purinergic receptor, P2X3 is an ATP-gated cation (VGSC) found in DRG neurons in neuropathic conditions. When agonized, this receptor activates voltage-gated sodium channel (VGSC) DRG neurons under neuropathic conditions. In a 2011 work by Mo et al, it was demonstrated that P2X3 purinoceptor-mediated currents induced by α, β meATP resulted in activation of TTX-sensitive VGSCs in neuropathic nociceptors. It is important to note that this was not observed in non-neuropathic nociceptors [12].

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Voltage–sensor domain

S2

S1

S4 Selectivity filter

S3

S6

S5

S4–S5 linker

Fig. 3  Single Nav subunit a voltage-sensor domain (VSD, S1-S4); a pore domain (PD, S5-S6); and a selectivity filter which exists between the P1 and P2 pore helices. Blocking ions and tetrodotoxin, bind at the extracellular mouth of the selectivity filter

The TTX-R Nav channels are Nav 1.5, 1.8 and 1.9 [13]. The relative resistance of Nav 1.5 to TTX is particularly advantageous because Nav 5 exists primarily in the heart. Avoiding blockade of Nav 1.5 would therefore avoid the cardiotoxic side effects present in nonselective Nav-blockers such as local anesthetics. Additionally, some TTX-S Nav channels have been found to be upregulated in certain conditions causing neuropathic pain. In humans, the expression of Nav 1.3 is increased in painful neuromas, after peripheral nerve injury, and in trigeminal neuralgia. Complex regional pain syndrome and post-herpetic neuralgia increase are associated with an upregulated, dermal expression of Nav  1.6 and Nav  1.7. Furthermore, increased expression of TTX-sensitive Nav channels has been found in animal models in states of inflammation-related neuropathic pain as well as diabetic neuropathy [7, 13]. In spinal nerve-ligated rats, there was an observed phenotypic switch of TTX-R channels to TTX-S ones [14]. In summary of TTX’s relationship to Nav channels, the channels that TTX would more favorably inhibit are the ones that are more common in pain conditions and the channels that may cause more serious side effects are much less sensitive to TTX.

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Studies on Therapeutic Potential In a review of TTX animal studies by Nieto et al., [15] 8 out of 11 experiments had positive effects on reduction or prevention of neuropathic pain. The surrogate markers of neuropathic pain in these studies were observations of mechanical or thermal allodynia with differing methods of inducing nerve damage. TTX application within the dorsal root ganglion of spinal nerve-ligated rats significantly reduced the activation of satellite glial cells  – cells that when activated, release messengers which contribute to neuropathic pain [16]. Newer TTX animal studies continue to show positive results. Alvarez and Levine [17] showed TTX could produce a small but significant reduction in neuropathic muscle pain following administration of oxaliplatin, a chemotherapy drug. Hong et al. [18] administered specially designed oral TTX pellets to rats and not only found it more effective in preventing mechanical and thermal allodynia than pregabalin and intramuscular TTX, but also had an improved safety profile via a higher LD50. The use of adjuvants or enhanced drug delivery methods for TTX poses an interesting question of whether TTX’s therapeutic index and safety profile can be further improved. Among the studies Melnikova et al. reviewed, [4] the efficacy and duration of action of TTX could be improved with co-application with local anesthetics, nanocarriers, vasoconstrictors, and chemical permeation enhancers (defined as molecules that increase lipid permeability). They found the safety profile to be most improved in cases where TTX was immobilized on nanocarriers and vasoconstrictors, the latter of which makes sense since vasoconstrictors are already often co-administered to reduce the systemic toxicity of local anesthetics. Other groups have tested capsaicin [19] and developed a polymer carrier for TTX, [20] both of which resulted in prolongation of nerve block with minimal to no local or systemic toxicity. With this data, future clinical trials involving TTX should naturally proceed to include the use of these particular adjuvants and/or drug delivery methods.

Clinical Application Clinical trials testing involving TTX as an analgesic have been limited to patients with chemotherapy-induced neuropathic pain (CINP). The pain from CINP often limits chemotherapeutic doses, decreasing the efficacy and success of treatment. In a dose-escalation study conducted among a small group of 24 participants, more than half of the TTX-dose regimens resulted in clinically significant reductions in pain lasting greater than 2 weeks [21]. A two-part trial spanning from 2008 to 2012 tested a 30 μg twice daily TTX regimen which demonstrated nominally significant pain reduction with transient mild adverse effects including nausea, numbness, injection site irritation, and tingling [22]. While the pain reduction was only nominal, the trial showed the duration of analgesia lasted 56.7 days in the treatment arm compared to 9.9  days in the placebo arm. More recently, a Phase 2 randomized control trial conducted in 2016 compared 4 cohorts of differing TTX regimens to placebo [23]. TTX was administered subcutaneously over 4 days to patients with

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CINP. Mean pain scores decreased the most with the 30 μg twice daily-dosed cohort with a tolerable side effect profile consisting of paresthesias, numbness, headache, and dizziness. Additionally, a Phase 1 trial involving liquid and lyophilized TTX has been tested, although the results were not posted [24]. Phase 3 trials and FDA approval involving subcutaneous TTX are ongoing, with Wex Pharmaceuticals currently branding tetrodotoxin for use in CINP as Halneuron [25].

Alternative Voltage-Gated Sodium Channel Blockers While TTX is seen as the most promising to utilize therapeutically as an analgesic, there are numerous other NaV channel blockers found in nature that could potentially be used to treat neuropathic pain: μ-conotoxin, saxitoxin, and anntoxin are but a few [26, 27]. Neosaxitoxin, an analog of saxitoxin, has been successfully tested in a Phase 1 clinical trial showing a tolerable side effect profile [28]. Anntoxin, an amphibian neurotoxin, has been identified as a TTX-S inhibitor and shown to have analgesic as well as anti-inflammatory properties in animal models [29]. These alternative  Nav  channel antagonists lag far behind TTX in terms of testing, but could serve as future avenues of expansion in the realm of neuropathic pain pharmaceutical development.

Summary TTX is a well-known neurotoxin produced by pufferfish, mollusks, crustaceans and other marine animals. It blocks Nav channel subtypes in a selective fashion and does not cross the blood-brain barrier. TTX does not cause seizures and central nervous system depression which are symptoms associated with local anesthetic toxicity. It can cause a variety of toxicities ranging from paresthesias to respiratory failure. TTX blocks sensitive Nav channels: Nav1–4, 6, and 7; but does not block resistant Nav  channels: Nav  5, 8 and 9. The latter characteristic gives TTX a particular advantage of over local anesthetics since these drugs are less selective and block the cardiac-associated Nav5 channels. This imparts a degree of cardioprotectivity to TTX. When activated, Nav channels contribute to neuronal excitation and subsequent excitotoxicity and neuropathic pain. Some TTX-S Nav channels are upregulated in certain neuropathic pain conditions (Table 1). Table 1  Summary of upregulated channel associations with specific neuropathic conditions Upregulated TTX-s Nav Channel Nav3 Nav6 Nav7

Syndrome Painful neuroma; Peripheral Nerve Injury; Trigeminal Neuralgia CRPS and Post-Herpetic Neuralgia CRPS and Post-Herpetic Neuralgia

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Inflammatory neuropathic pain and diabetic neuropathy are associated with increased expression of TTX-S Nav channels. Phenotypic switching of channel sensitivity profiles, i.e., a change from TTX-R to TTX-S status has been observed in spinal nerve ligation neuropathic pain preparations in a murine model. Early preclinical studies of TTX show efficacy of this neurotoxin in murine models of mechanical or thermal allodynia. TTX reduces the neuropathic pain generating capability of satellite glial cells when applied to the murine DRG.  TTX has shown some effectiveness in the treatment of chemotherapy-induced peripheral neuropathy. Oral preparations have been used in murine models to reduce mechanical and thermal allodynia. Co-application of TTX with local anesthetics, nanocarriers, vasoconstrictors and chemical permeation enhancers have increased the effectiveness of TTX. The largest beneficial effect is seen with nanocarriers and vasoconstrictors. Clinical trials testing follows the direction indicated by the most successful work in animal models, i.e., examination of the value of the drug in treating CINP. Other neurotoxins are being tested on a worldwide basis. These include μ-conotoxin, saxitoxin, and anntoxin. These may prove useful in the treatment of neuropathic pain in the more distant future.

References 1. DiBonaventura MD, et al. The prevalence of probable neuropathic pain in the US: results from a multimodal general-population health survey. J Pain Res. 2017;10:2525–38. 2. Wiffen PJ, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews. Cochrane Database Syst Rev. 2013;11:CD010567. 3. Clark GC, et al. Friends or foes? Emerging impacts of biological toxins. Trends Biochem Sci. 2019;44(4):365–79. 4. Melnikova DI, Khotimchenko YS, Magarlamov TY. Addressing the issue of tetrodotoxin targeting. Mar Drugs. 2018;16(10):352. 5. Jal S, Khora SS. An overview on the origin and production of tetrodotoxin, a potent neurotoxin. J Appl Microbiol. 2015;119(4):907–16. 6. McGlothlin JW, et al. Parallel evolution of tetrodotoxin resistance in three voltage-gated sodium channel genes in the garter snake Thamnophis sirtalis. Mol Biol Evol. 2014;31(11):2836–46. 7. Dib-Hajj SD, et al. Sodium channels in normal and pathological pain. Annu Rev Neurosci. 2010;33:325–47. 8. Catterall WA. A 3D view of sodium channels. Nature. 2001;409(6823):988–9, 991. 9. Shaya D, et al. Structure of a prokaryotic sodium channel pore reveals essential gating elements and an outer ion binding site common to eukaryotic channels. J Mol Biol. 2014;426(2):467–83. 10. Hille B.  The receptor for tetrodotoxin and saxitoxin. A structural hypothesis. Biophys J. 1975;15(6):615–9. 11. Noda M, et al. A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II. FEBS Lett. 1989;259(1):213–6. 12. Mo G, et  al. Neuropathic Nav1.3-mediated sensitization to P2X activation is regulated by protein kinase C. Mol Pain. 2011;7:14. 13. Ogata N, Ohishi Y.  Molecular diversity of structure and function of the voltage-gated Na+ channels. Jpn J Pharmacol. 2002;88(4):365–77. 14. Yin R, et al. Voltage-gated sodium channel function and expression in injured and uninjured rat dorsal root ganglia neurons. Int J Neurosci. 2016;126(2):182–92.

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15. Nieto FR, et  al. Tetrodotoxin (TTX) as a therapeutic agent for pain. Mar Drugs. 2012;10(2):281–305. 16. Xie W, Strong JA, Zhang JM. Early blockade of injured primary sensory afferents reduces glial cell activation in two rat neuropathic pain models. Neuroscience. 2009;160(4):847–57. 17. Alvarez P, Levine JD. Antihyperalgesic effect of tetrodotoxin in rat models of persistent muscle pain. Neuroscience. 2015;311:499–507. 18. Hong B, et  al. Effect of tetrodotoxin pellets in a rat model of postherpetic neuralgia. Mar Drugs. 2018;16(6):195. 19. Shomorony A, et al. Prolonged duration local anesthesia by combined delivery of capsaicinand tetrodotoxin-loaded liposomes. Anesth Analg. 2019;129(3):709–17. 20. Zhao C, et al. Polymer-tetrodotoxin conjugates to induce prolonged duration local anesthesia with minimal toxicity. Nat Commun. 2019;10(1):2566. 21. Hagen NA, et al. An open-label, multi-dose efficacy and safety study of intramuscular tetrodotoxin in patients with severe cancer-related pain. J Pain Symptom Manag. 2007;34(2):171–82. 22. Hagen NA, et  al. Tetrodotoxin for moderate to severe cancer-related pain: a multicen tre, randomized, double-blind, placebo-controlled, parallel-design trial. Pain Res Manag. 2017;2017:7212713. 23. Goldlust S, et  al. Tetrodotoxin (TTX) for chemotherapy induced neuropathic pain (CINP): a randomized, double-blind, dose-finding, placebo controlled, multicenter study (S17.003). Neurology. 2016;86(16 Supplement):S17.003. 24. ClinicalTrials.gov. Comparison study of liquid and lyophilized formulations of subcutaneous tetrodotoxin (TTX) in healthy volunteers, in ClinicalTrials.gov [Internet]. 2012, ClinicalTrials. gov Internet. 25. Wong D, Korz W.  Tetrodotoxin treatment of mechanical allodynia in rats with oxaliplatin and vincristine-induced neuropathy. In: American Pain Society 34th annual scientific meeting. Palm Springs; 2015. 26. Hamad MK, et al. Potential uses of isolated toxin peptides in neuropathic pain relief: a literature review. World Neurosurg. 2018;113:333–347 e5. 27. Mattei C, Legros C. The voltage-gated sodium channel: a major target of marine neurotoxins. Toxicon. 2014;91:84–95. 28. Lobo K, et al. A phase 1, dose-escalation, double-blind, block-randomized, controlled trial of safety and efficacy of neosaxitoxin alone and in combination with 0.2% bupivacaine, with and without epinephrine, for cutaneous anesthesia. Anesthesiology. 2015;123(4):873–85. 29. Wei L, et al. Analgesic and anti-inflammatory effects of the amphibian neurotoxin, anntoxin. Biochimie. 2011;93(6):995–1000.

Epigenetic Alterations in the Nervous System in Neuropathic Pain Daryl I. Smith

Genetic material is organized in the cellular nucleus in a way that makes it susceptible to post-transcriptional modifications. DNA is wrapped around highly basic protein octamers, histones, to form nucleosomes and, subsequently, chromatin. Histones themselves may be post- translationally modified which may then serve to regulate important chromatin-based processes [1]. Epigenetic modification of chromatin is responsible for cellular plasticity which allows for the cellular response to certain environmental cues. This chapter discusses this principle and subsequent genomic changes that result in neuronal hypersensitivity. An essential regulator of developmental expression is the Polycom repressive system (PRC). It is comprised of three multi-protein repressive complexes (PRC1, PRC2, and PhoRC). Along with Trithorax (Trx) group proteins, these chromatin-­ modifying factors have been shown to regulate several cellular processes. They display the ability to regulate chromatin at multiple levels including three-dimensional organization of the genome [2]. Removal of these enzymes can lead to alterations in gene expression. Polycom repressive complex 1 (PRC1) mono-ubiquitylates histone H2A at the lysine in the 119th position (H2AK119 ub1). Polycomb repressive complex 2 (PRC2) is a Class 2 methyltransferase. It mono-, di-, and tri-methylates histone H3 at lysine 27 (H3K27me1, H3K27me 2, H3K27me 3). The methylation occurs at regions of the DNA where a cytosine nucleotide is followed by a guanine nucleotide. This is known as a CpG site or a CG site and sections of the genome where they are found in high numbers are known as CG or CpG islands. Acetylation of histone octamers leads to a relaxed configuration and subsequent gene expression. Deacetylation and methylation lead to a condensed configuration and suppression of gene expression [3] (Fig. 1).

D. I. Smith (*) University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_5

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Transcription

Translation

Glutamate Gene products Opioid peptide GABA 10

Opioid receptor GABA receptor

Proinflamatory cytokines

Glial cell

Fig. 1  Role of viral vector therapy in the treatment of chronic pain. Therapeutic genes encoded in viral vectors infect target cells and express antinociceptive substances. The vector (circular construct with red genetic material, e.g. for IL-4 or IL-10, in the upper left of the image) binds to the target cell where it is transcribed in the nucleus then translated in the cytoplasm. Important anti-­ inflammatory products such as IL-4 and IL-10 bind to the target cell where the desired effects may be accomplished. Viral vectors may also deliver antisense genes which can prevent an increase in the expression of pronociceptive proteins such as Nav1.7 and thereby reduce inflammatory hyperalgesia

PRC2 I s comprised of 3 core subunits: EED, EZH2 and SUZ12; and 3 cofactors: JARID2, AEBP2, and PbAp46/48. The subunits exhibit a degree of codependence in that some are required for the function of others. For example, while EZH2 is the subunit with catalytic activity in the methyltransferase reaction, it requires EZH2 in order to function in this role. Likewise, EZH2 requires the SUZ12 subunit to function in its enzyme capacity as well. PRC2 is found most often co-occupying the transcription factor (TF) promoters for genes involved in cell differentiation and development. The trimethylation event blocks the access of the TF promoter to the RNA polymerase required to express the gene. Repressing the transcription factor will, in turn, inhibit expression of the gene with which the TF interacts. PRC2 has been shown to silence the expression of genes that regulate cell cycle checkpoints, differentiation, cell adhesion, and DNA damage response, thus promoting cancer cell growth and proliferation PRC1 and PRC2 recognize target gene promoters that are associated with cytosine-­guanine DNA linkages (CpG islands or CGIs). The result is the formation

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of Polycomb-chromatin domains. When these structures are perturbed, alterations in the levels of H2AK119ub1 andH3K27me can occur with resultant inappropriate expression of polycomb target genes. These disruptions at the molecular level are believed to be responsible for developmental abnormalities as well as other human disease states [4]. In general, acetylation of octamers, e.g., by histone acetyltransferases leads to a relaxed configuration and subsequent gene expression. Histone deacetylation and methylation, usually accomplished by histone deacetylase (HDAC) and histone methyltransferase (HMT), respectively, lead to a condensed configuration and suppression of gene expression. It should be noted that these epigenetic modifications effect gene expression alterations without altering the underlying DNA sequence itself. An organism’s epigenetic profile differs from the genetic profile in that the genetic profile is constant and unchanging whereas the epigenetic profile is the result of alterations that occur in response to internal as well as external stimuli. These stimuli include drug abuse, psychological stress, diet and exercise [3]. Perhaps the final common pathway in the transition of acute pain to chronic or neuropathic pain is transformation of neural activation patterns as a result of changes in channel structural conformation and/or the chemical components of the cascades initiated by their activation. The DNA methylation event plays a critical role in the reprogramming of the DRG and thus contributes to nerve injury-induced chronic pain. Restoring baseline DNA methylation status may represent a new therapeutic approach to treat neuropathic pain [5]. Pan et al., described the prolonged hyperactivity of damaged primary afferent nerves and sensory neurons located in the dorsal root ganglion [6]. This was iterated by Liu et  al., in 2000 when they described genetically induced changes in firing properties of DRG neurons subsequent to spinal injury. The sustained changes that result in long-term hypersensitivity suggests that a multitude of genetic changes occur and are necessary to maintain these neuronal firing patterns. Xiao et  al., found that the expression of 122 genes and 51 expressed sequence tags is strongly changed; and that these genes are comprised of a molecularly diverse group. These include neuropeptides, receptors, ion channels, signal transduction molecules, synaptic vesicle proteins, etc. The up-regulation of the gamma-aminobutyric acid (A) receptor alpha subunit; the peripheral benzodiazepine receptor, nicotinic acetylcholine receptor α 7 subunit; the P2Y1 purinoceptor; the sodium channel β2 subunit; and the L-type Ca++ channel alpha 2 δ-1 subunit were the critical genetic alterations across this epigenetic event in the DRG following nerve injury [7]. The specific criticality of these epigenetic mechanisms was demonstrated by Matsuhita et al., in 2013, then later by Laumet et al., in 2015 [8, 9]. In the neural injury setting, Schwann cells undergo significant gene expression changes as well. These changes require individual transcription factors and cognate enhancers that serve to integrate the actions of multiple transcription factor inputs which regulate associated genes. Svaren et al., examined injury-induced as well as injury-suppressed enhances and identified dynamic enhancer changes that were involved in post-injury gene expression. Their goal was to determine how peripheral nerve injury (PNI) alters the global transcription program. The group focused upon injury-induced changes in histone H3K27 acetylation. They investigated the

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function of PRC2 in Schwann cell development following deletion of EED. EED-­ modulated PRC2 inactivation resulted in the induction of a subset of nerve injuryassociated genes that are normally repressed by H3K27 trimethylation and that the removal of H3K27 trimethylation is necessary for part of the Schwann cell injury response [10]. SETD7 is a histone-lysine N-methyltransferase that, like PCR2, can affect gene expression through its activity on histone. In this case this regulation is critical to the development of spinal microgliosis and neuropathic pain following peripheral nerve injury. The monomethylation of histone H3 lysine 4 (H3K4 me1) by SETD7 in a nerve injury environment was characterized by Shen et al., in 2019. In this study, SETD7 knockdown via intrathecal lentivirus shRNA prior to CCI prevented microgliosis and neuropathic pain. This was in direct contrast to the situation in which lentiviral SETD7 delivered via transduction exacerbated the symptoms. SETD7 was also found to regulate H3K4me1 levels and the expression of inflammatory mediators. The SETD7 inhibitor PFI-2 suppressed the lipopolysaccharide-induced morphology of primary microglia and the expression of the inflammatory genes Ccl2, IL-6 and IL-1β. In addition, PFI-2 alleviated CCI-induced neuropathic pain, though only in males. Nevertheless, the study revealed that DNA methylation played not only a significant role in neuropathic pain development but also that manipulation of its critical enzymatic components may be suitable targets for anti-neuropathic pain therapy [11]. Other histone targeting enzymes have been studied with respect to neuropathic pain and in the light of neuronal synaptic plasticity. Jumanji C domain 6 protein (JMJD6) is a histone demethylase. In the CCI murine model, introduction of a lentiviral vector that overexpresses JMDJD6 (LV-JMJD6) resulted in the attenuation of neuropathic pain behavior as assessed by the mechanical withdrawal threshold and thermal withdrawal latency. JMJD6  in the control state is lowered following CCI. Intrathecal injection of LV-JMJD6 also markedly decreased the expression of the spinal NF-κB phosphorylated subunit, the active form of the protein complex. This subsequently resulted in a decrease of its downstream pain-associated effector including IL-1β, TNF-α and VEGF. They concluded that JMJD6 may exert its therapeutic effect by regulating activation of NF-κB following neural injury [12]. The authors do not however propose a description of exactly where the JMJD6-critical genetic demethylation event occurs. In another epigenetic event description. Wang et al., used lumbar spinal cord and ventral tegmental area preparations in a murine model of neural injury to examine the role played by the proinflammatory cytokine, macrophage migration inhibitory factor (MIF), in the regulation of neuropathic hypersensitivity. Following sciatic nerve CCI, significant upregulation of MIF occurred in a time-dependent manner. The level of MIF is inhibited by the small molecule antagonist, (S, R) 3-(4-hydroxyphenyl)-4,5-dihyro-5-isoxazole acetic acid methyl ester (ISO-1). The nerve injury event induces methylation of the tyrosine hydroxylase gene (Th) promoter CpG site in the L-SC and VTA areas. This methylation is prevented by ISO-1 administration. ISO-1 was also found to decrease G9a/SUV39H1 and H3K9me2/ H3K9me3 enrichment in Th promoter region in the post CCI environment. The

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work implicated MIF as an attenuator of peripheral nerve injury-induced hypersensitivity. This attenuation seems to occur via MIF mediation of the Th gene methylation, which occurs via G9a/SUV39H1-associated H3K9 methylation [13]. The triazole derivative, compound MG17 reduced nociceptive responses in a streptozotocin-induced, diabetic murine model of diabetic peripheral neuropathy and neuroinflammation concomitant assay for proinflammatory cytokines revealed significant regulation of IL-6 and TNF-α but not IL-1β. The specific genetic mechanism by which compound MG-17 inhibited cytokine upregulation was not defined but given the potential for possible clinical use epigenetic study for this compound is warranted [14]. Caloric reduction (CR) appears to slow physiologic signs of ageing and possibly mediate neuropathic pain in murine models. In a 2018, Liu et al., subjected rats to a CR diet setting of CCI. The study revealed that the enzyme responsible for deacetylation of proteins, especially in histone modifications, sirtulin-1was increased. This resulted in the suppressed activation of NF-κB with resultant suppression of IL-1β. It is interesting to note that CR also decreased the phosphorylation of N-methyl-d-­ aspartate (NMDA) receptor subunits and decreased sensory neuronal excitability. Given these findings, the group concluded that CR could be of benefit in patients with neuropathic pain [15]. The antihyperglycemic drug, metformin, was studied to examine its ability to alter DNA methylation profiles in human blood cells. One hundred twenty-five differentially methylated CpGs were analyzed. Of these, 11 CpGs were selected based upon the most consistent changes in the DNA methylation profile. These were: POFUT2, CAMKK1, EML3, KIAA1614, UPF1, MUF4, LOC727982, SIX3, ADAM8, SNORD12B, VPS8; and several differentially methylated regions as novel, potential epigenetic targets of metformin expression of NADPH oxidase (NOX) enzymes. These enzymes generate reactive oxygen species and play a significant role in the cellular and molecular injury observed in diabetic neuropathy. There are 7 isoforms of NOX but only NOX5 is known to exist in humans. Eid et  al., determined that the epigenetic methylation status of NOX5  in cutaneous nerve fibers and sural nerve biopsies of diabetic patients. The subjects were divided into two groups based upon sural nerve myelinated fiber density. The groups were regenerators, or those patients who demonstrated significant nerve regeneration; and degenerators, or those who showed significant nerve degeneration. There was significant hypomethylation at the multiple CpG islands in NOX5 promoter in the degenerator group. In the regenerator group there was no such hypomethylation. This lead to the conclusion that hypomethylation of NOX5 promoter was associated with an increase in NOX5 expression with subsequent increase of ROS greater cellular and molecular injury [16]. Finally, the neural balance between facilitation and inhibition was studied in relation to central sensitization in the setting of neural injury by Wang et  al., in 2016. They looked at the molecular mechanism involved in dopaminergic transmission in the descending inhibitory antinociceptive pathway. Specifically, they proposed that the component of neuropathic pain which was comprised of reduced dopaminergic, descending inhibitory pathway input was likely the result of

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downregulation of tyrosine hydroxylase expression by methylation of its TH gene at G9a/Glp complex sites. Indeed, following nerve injury in murine models. They found that the methyltransferase G9a/Glp complex mediates at least in part, dopaminergic transmission by methylating Th in peripheral nerve injury [17]. MicroRNAs (miRNAs) are a subtype of noncoding functional RNA that are transcribed from DNA. They are approximately 20 nucleotides long and alter protein expression through suppression of protein translation [3]. The role of miRNAs in peripheral pain pathways include nociceptor excitability, pain threshold changes, and the expression of sodium channels. The mechanisms by which miRNAs alter pain thresholds appear to include transcriptional deficits that lead to repression of gene expression. In essence, the cytoplasmic ribonuclease III Dicer produces double stranded RNAs (miRNAs and siRNAs). Individual miRNAs may regulate up to hundreds of different mRNA transcripts [18]. These miRNAs have the ability to both positively and negatively regulate translation [19, 20]. Specific miRNAs in the development of neuropathic pain have been describe. These have frequently examined in murine models. For example, miR-133a-3p was shown to play a role in the streptozotocin-induced diabetic neuropathy, murine model. Its ability to upregulate NF-κB p50 and MKP3 expression was shown indirectly when miR-133a-3p antagonize (an inhibitory mimic of the miRNA) reduced NF-κB p50 and MKP3 expression; and reduced neuropathic pain behavior [21]. The miR-134-5p was shown to strongly alleviated neuropathic pain behavior in a murine model induced by CCI of the sciatic nerve. Mechanistically, upregulation of miR-134-5p significantly repressed expression of the inflammatory cytokines, IL-6, IL-1β, and TNF-α among others [22]. miR-340-5p appears to be down-regulated in spinal cord tissues and microglial cells following CCI which correlated with increased neuropathic behavior. Overexpression of miR-340-5p, however led to a decrease in expression of COX-2, IL-1β, TNF-α and IL-6; [23] and miR-98 has been shown to repress neuropathic pain development again by repressing cytokine members IL-6, IL-1β, and TNF-α. In this setting STAT3 appears to be the direct target of miR-98 with STAT-3 expression inhibited by miR-98 overexpression [24]. Similarly an anti-neuropathic effect is also the result of miR-129-5p expression. This miRNA suppresses the expression of the high mobility group protein B1 (HMGB1) and proinflammatory cytokines [25]. In a 2020 study by Qiu et al., the effect of miR-101 on pain hypersensitivity in CCI rat models was examined. The study specifically examined neuropathic pain behavior; and used the expression of IL-1β, IL-6, and TNF-α as markers of inflammation. When miR-101 was overexpressed, IL-1β, IL-6 and TNF-α was also expressed in increased quantities. The common pathway in the expression of the cytokines appears to be the inhibition of MKP1 expression and the upregulation of MAPK with subsequent activation of the cytokine cascade. In this way, it is believed that miR-101 promotes hypersensitivity and the inflammatory response in murine microglia [26]. Clearly this must be replicated in humans if it is to acquire clinical relevance. Interestingly, the commonly used drug α2 agonist drug,

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dexmedetomidine, appears to regulate miR-101. The drug is known to function as a potent anti-­anxiety agent, a sedative, and as an analgesic. Recently it has also been shown to function as regulation of miR-101 with subsequent decrease in the expression of IL-6, IL-8, and TNF-α. It is believed that dexmedetomidine regulates the miR-101/NF-κB axis in the CCI murine model [27].

Conclusion Epigenetic modification of chromatin is responsible for cellular plasticity which allows for the cellular response to certain environmental cues. The polycom repressive system regulates several cellular processes and regulates chromatin at multiple levels including three-dimensional organization of the genome. Removal of these enzymes can lead to alterations in gene expression. Polycom repressive complex 2 (PRC2) mono-, di- and tri- methylates histone H3 (H3K27me1, H3K27me2, and H3K27me3, respectively) at lysine 27. PRC2 can silence the expression of genes that regulate the expression of genes that regulate cell cycle checkpoints, differentiation, cell adhesion and DNA damage response. In the setting of neuropathic pain DNA methylation plays a critical role in the reprogramming of the DRG and thus contributes to nerve injury. Protein expression as a result of epigenetic events may alter the structure and function of neuropeptides, receptors, ion channels, signal transduction molecules, and synaptic vesicle proteins. Up regulation of the GABA receptor α subunit, the peripheral benzodiazepine receptor, the nAChR α7 subunit, the P2Y1 purinoceptor, the sodium channel β2 subunit, and the L-type Ca++ channel alpha 2 δ-1 subunit have recently been identified as protein structures in the DRG that are epigenetically altered following nerve injury. Schwann cells also undergo gene expression changes following nerve injury. Trimethylation of the H3H27 histone is critical to the baseline status of this complex which represses a subset of nerve injury-associated genes. Demethylation at this site is necessary for the Schwann cell injury response. The SETD7 histone-lysine N-methyltransferase methylates histone H3 lysine 4. This methylation is critical to the development of spinal microgliosis and the expression of inflammatory mediators following neural injury. Other histone targeting enzymes that are critical to neuropathic pain development and prevention have been identified. JMJD6 is a histone demethylase that actively decreases the expression of NF-κB and the resultant signaling cascade that leads to the expression of neuropathy-­ critical cytokines. The role of miRNA in peripheral pain pathways and neuropathic pain include affecting nociceptor excitability; alterations in pain thresholds, and altering the expression of sodium channels. They have the ability to both positively and negatively regulate translation. The miRNAs that have been shown to decrease neuropathic pain, at least in murine models are miR-133a-3p, miR-134-5p, miR-­340-5p, and miR-98. While miR-101 promotes hypersensitivity and the inflammatory

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response in murine microglia via the upregulation of MAPK with subsequent activation of the cytokine cascade. Caloric reduction, metformin, the triazole derivative MG17 and dexmedetomidine have been shown to have positive effects upon neuropathic pain via epigenetic processes in animal models.

References 1. Atlasi Y, Stunnenberg HG. The interplay of epigenetic marks during stem cell differentiation and development. Nat Rev Genet. 2017;18(11):643–58. 2. Schuettengruber B, Bourbon HM, Di Croce L, et  al. Genome regulation by polycomb and trithorax: 70 years and counting. Cell. 2017;171(1):34–57. 3. Odell DW. Epigenetics of pain mediators. Curr Opin Anaesthesiol. 2018;31(4):402–6. 4. Blackledge NP, Fursova NA, Kelley JR, et al. PRC1 catalytic activity is central to polycomb system function. Mol Cell. 2020;77(4):857–874 e9. 5. Garriga J, Laumet G, Chen SR, et  al. Nerve injury-induced chronic pain is associated with persistent DNA methylation reprogramming in dorsal root ganglion. J Neurosci. 2018;38(27):6090–101. 6. Pan HL, Eisenach JC, Chen SR. Gabapentin suppresses ectopic nerve discharges and reverses allodynia in neuropathic rats. J Pharmacol Exp Ther. 1999;288(3):1026–30. 7. Xiao HS, Huang QH, Zhang FX, et al. Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci U S A. 2002;99(12):8360–5. 8. Laumet G, Garriga J, Chen SR, et al. G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition. Nat Neurosci. 2015;18(12):1746–55. 9. Matsushita Y, Araki K, Omotuyi O, et al. HDAC inhibitors restore C-fibre sensitivity in experimental neuropathic pain model. Br J Pharmacol. 2013;170(5):991–8. 10. Svaren J, Hung HA, Ma KH, et al. Chromatin dynamics in Schwann cells after nerve injury. Glia. 2015;63:E31. 11. Shen Y, Ding Z, Ma S, et al. SETD7 mediates spinal microgliosis and neuropathic pain in a rat model of peripheral nerve injury. Brain Behav Immun. 2019;82:382–95. 12. Wen C, Xu M, Mo C, et al. JMJD6 exerts function in neuropathic pain by regulating NF-κB following peripheral nerve injury in rats. Int J Mol Med. 2018;42(1):633–42. 13. Wang X, Ma S, Wu H, et al. Macrophage migration inhibitory factor mediates peripheral nerve injury-induced hypersensitivity by curbing dopaminergic descending inhibition. Exp Mol Med. 2018;50(2):e445. 14. Matharasala G, Samala G, Perumal Y.  MG17, a novel triazole derivative abrogated neuroinflammation and related neurodegenerative symptoms in rodents. Curr Mol Pharmacol. 2018;11(2):122–32. 15. Liu Y, Ni Y, Zhang W, et al. Anti-nociceptive effects of caloric restriction on neuropathic pain in rats involves silent information regulator 1. Br J Anaesth. 2018;120(4):807–17. 16. Eid S, Hayes JM, Guo K, et al. NOX, NOX, are you here? the emerging role of NOX5 in diabetic neuropathy. Diabetes. 2018;67:LB8. 17. Wang N, Shen X, Bao S, et  al. Dopaminergic inhibition by G9a/Glp complex on tyrosine hydroxylase in nerve injury-induced hypersensitivity. Mol Pain. 2016;12:1744806916663731. 18. Zhao J, Lee MC, Momin A, et al. Small RNAs control sodium channel expression, nociceptor excitability, and pain thresholds. J Neurosci. 2010;30(32):10860–71. 19. Vasudevan S, Tong Y, Steitz JA. Cell-cycle control of microRNA-mediated translation regulation. Cell Cycle. 2008;7(11):1545–9. 20. Bartel DP.  MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.

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21. Chang LL, Wang HC, Tseng KY, et al. Upregulation of miR-133a-3p in the sciatic nerve contributes to neuropathic pain development. Mol Neurobiol. 2020;57(9):3931–42. 22. Ji LJ, Su J, Xu AL, et al. MiR-134-5p attenuates neuropathic pain progression through targeting Twist1. J Cell Biochem. 2018; https://doi.org/10.1002/jcb.27486. 23. Gao L, Pu X, Huang Y, et al. MicroRNA-340-5p relieved chronic constriction injury-induced neuropathic pain by targeting Rap1A in rat model. Genes Genom. 2019;41(6):713–21. 24. Zhong L, Fu K, Xiao W, et al. Overexpression of miR-98 attenuates neuropathic pain development via targeting STAT3 in CCI rat models. J Cell Biochem. 2018; https://doi.org/10.1002/ jcb.28076. 25. Tian J, Song T, Wang W, et  al. miR-129-5p alleviates neuropathic pain through regulating HMGB1 expression in CCI rat models. J Mol Neurosci. 2020;70(1):84–93. 26. Qiu S, Liu B, Mo Y, et al. MiR-101 promotes pain hypersensitivity in rats with chronic constriction injury via the MKP-1 mediated MAPK pathway. J Cell Mol Med. 2020;24:8986. 27. Zhang W, Yu T, Cui X, et al. Analgesic effect of dexmedetomidine in rats after chronic constriction injury by mediating microRNA-101 expression and the E2F2-TLR4-NF-kappaB axis. Exp Physiol. 2020;105:1588.

Part II Neuropathic Syndromes

Pathogenesis of Neuropathic Pain: Diagnosis and Treatment May Wathiq Al-Khudhairy, Abdullah Bakr Abolkhair, and Ahmed Osama El-Kabbani

Complex Regional Pain Syndrome Introduction Complex regional pain syndrome (CRPS) has always been viewed as a challenge, sparking confusion and intimidation among researchers, clinicians, and epidemiologists during the past decades, mostly due to their unusual symptomology, poorly understood mechanisms, vague definitions and treatment resistances. Recently however, advances made in uncovering and identifying the interplay of multiple mechanisms underlying the pathogenesis of CRPS have cleared the fog surrounding it and gave way to further strides in proper diagnosis and management of this condition.

Definition CRPS is defined as a chronic disabling pain disorder typically developing in extremities; it is disproportionate (in time or severity) to an inciting event such as soft tissue injury, fracture, or surgery. Characterized by neuropathic pain (burning pain, M. W. Al-Khudhairy Oral Diagnosis and Maxillodacial Surgery Department, Riyadh Elm University, Riyadh, Saudi Arabia e-mail: [email protected]; [email protected] A. B. Abolkhair (*) Department of Anesthesia, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia e-mail: [email protected] A. O. El-Kabbani Department of Anesthesiology, Matareya Teaching Hospital, Cairo, Egypt © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_6

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allodynia, hyperalgesia) along with sensory, autonomic (skin color, temperature, sweating alterations), trophic (skin, hair, nail changes) and motor abnormalities (decreased strength, limited range of motion, tremor) [1]. CRPS is subdivided into CRPS type I, also known as reflex sympathetic dystrophy, indicating the absence of a clinically identifiable peripheral nerve injury, and CRPS type II, previously known as causalgia, reflecting the presence of a major nerve lesion [2]. However, despite this diagnostic distinction, both types share similar signs, symptoms, and pathophysiologic mechanisms [1].

Pathophysiological Mechanisms Multiple pathophysiological factors are believed to contribute to the development of CPRS, with interplay of peripheral, central, genetic as well as psychological mechanisms in causing the characteristic signs and symptoms of this disorder. The most widely accepted and documented peripheral mechanisms in CPRS include peripheral sensitization and altered cutaneous innervation. Peripheral sensitization occurs due to hyper-excitability of afferent nociceptors caused by a nerve injury, accompanied by changes in the expression of neurotransmitters and pro-nociceptive neuropeptides such as substance P and bradykinin [3, 4]. This results in an increase in firing of nociceptors at rest as well as in response to nociceptive stimuli, along with a decrease of the firing threshold in response to mechanical and thermal stimuli, contributing to the development of characteristic CPRS features of hyperalgesia and allodynia [3–5]. This is supported by the observation of local hyperalgesia in the affected limb of CRPS patients and its absence in the unaffected limb, measured by quantitative sensory testing [6]. Altered cutaneous innervation has been found even in CPRS-I patients, where no clinical signs of nerve injury are identified, suggesting the presence of some form of initial nerve injury triggering CRPS [7, 8]. This is evident by reduced density of epidermal neurites (especially nociceptive fibers such as C and A-delta fibers) in skin biopsies obtained from the affected limb relative to the contralateral unaffected limb, pain-free location on the same limb and healthy controls, along with reduced innervation of hair follicles and sweat glands [8, 9]. Central sensitization and brain plasticity are two central mechanisms believed to contribute to the development of CPRS. The persistent hyper-excitability of nociceptive neurons at the spinal cord resulting from tissue damage or nerve injury is called central sensitization, and is due to the persistent release of neuropeptides (substance P and bradykinin) and excitatory neurotransmitters (glutamate) [10, 11]. This leads to an exaggerated response to nociceptive stimuli (hyperalgesia) as well as to non-painful stimuli (allodynia), and can be measured through the increased excitability of spinal neurons that are triggered by repeated stimulations similar to the firing rate of nociceptive fibers, a process termed windup [1, 10, 12]. CPRS patients have been found to suffer from a greater windup to repeated stimuli applied to the affected areas versus other areas that are not affected [13, 14].

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Studies have shown the presence of functional alterations in the central representation of somatosensory sensations of patients with CRPS, specifically, reduced size of representation of the affected limb [15–18]. This correlates with the observed clinical effects of hyperalgesia, increased pain intensity, impaired tactile discrimination and sensations beyond the stimulated nerve distribution, the latter of which helps explain the non-dermatomal distribution of pain noted in CRPS [17, 19, 20]. Moreover, these changes in the somatotopic map organization have also been found to revert to normal after successful treatment of the condition, supporting the role of brain plasticity in the development of CRPS as opposed to having these brain changes before the development of this condition [1, 16, 18]. Furthermore, alterations in the activity of sensory, motor and affective brain regions have been displayed via neuroimaging in CRPS patients compared with healthy controls or stimulation of the contralateral limbs, as indicated by several studies [21–23]. Autonomic abnormalities in CRPS are best explained via a mixed (peripheral and central) mechanism in the pathogenesis of this condition and are due to impairment of sympathetic and catecholaminergic functions. Peripheral impairment of sympathetic function such as sympathetic denervation (vasodilation following transection of sympathetic fibers) and denervation hypersensitivity (subsequent increased sensitivity to circulating catecholamines) are believed to be the means behind blood flow abnormalities within the area of a lesioned nerve in CRPS-II [24]. Expression of adrenergic receptors on nociceptive fibers after nerve injury helps explain the latter (denervation hypersensitivity), linking sympathetic nervous system (SNS) outflow to directly triggering nociceptive signals (pain) as well as underlying common autonomic features of CPRS (cold, bluish limb), in a process termed sympatho-afferent coupling [1, 25, 26]. This is demonstrated via an increase in the intensity of CRPS-pain following activation of SNS vasoconstrictor response via forehead cooling, or intradermal injection of catecholamines (norepinephrine) in the affected area, as indicated by several studies [27, 28]. This also reflects that CPRS pain and other characteristic symptoms could be sympathetically maintained. However, due to the absence of a clinically identifiable nerve lesion in CRPS I and the presence of autonomic symptoms beyond the distribution of the lesioned nerve in CRPS-II, peripheral impairment of sympathetic function cannot solely account for vasomotor and sudomotor dysfunction observed in CRPS [24]. This is where evidence of central autonomic reorganization observed in CRPS patients comes into play, as displayed by increased resting sweat output, and heightened thermoregulatory and axon reflex-sweating from the sweat glands, where –unlike blood vesselsdenervation hypersensitivity do not develop [24]. In other work studying cutaneous sympathetic innervation in CRPS-I patients, vasoconstriction to cold stimuli has been found to be absent in the affected side of patients with acute (warm-type) CRPS, but was exaggerated in patients with chronic (cold-type) CRPS despite concomitant portrayal of lower catecholamine (norepinephrine) levels on the affected side concurrent with a diminished local SNS outflow [27, 29–31]. This dysfunctional SNS thermoregulation point towards the location of such disturbed reflex activity being in the central nervous system (CNS) and that excessive SNS outflow is not solely responsible for the CRPS symptoms that have been linked to SNS

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activity [1, 24]. In fact, these findings of exaggerated vasoconstriction and sweating suggest hypersensitivity to circulating catecholamine levels possibly due to compensatory up-regulation of peripheral adrenergic receptors expected in the decreased SNS outflow noted earlier, and support the evidence of altered SNS and catecholaminergic function in CPRS patients [1, 31, 32]. Nevertheless, studies indicating the presence of dysfunctional endothelial-dependent vasodilation along with altered levels of endothelin-1, nitric oxide and nitric oxide synthase point towards additional non-SNS mechanisms underlying vascular abnormalities seen in CRPS [9, 33–36]. Another proposed mixed (central and peripheral) mechanism in the pathogenesis of CRPS include aberrant inflammation, which was believed to explain the findings behind successful corticosteroid treatment in some patients with acute CRPS [37, 38]. Aberrant inflammation in CRPS is thought to arise via two sources, classic and neurogenic inflammatory mechanisms. In classic inflammation, which occurs after tissue injury, white blood cells (lymphocytes and mast cells) release pro-­inflammatory cytokines such as interleukins and tumor necrosis factor (TNF) resulting in vasodilation, plasma leakage, and tissue edema [1, 3]. Several studies examining pro-inflammatory cytokines in CRPS patients have indicated significant increases in TNF-α, interleukin-1 ß, −2, and − 6 in local blister fluid, plasma and cerebrospinal fluid (CSF), compared to healthy controls and non-CRPS pain patients [21, 39–42]. Of these cytokines, TNF-α plays a major role in inflammation through direct pro-nociceptive actions, as well as inducing the production of other cytokines [43]. Increased levels of pro-inflammatory neuropeptides including calcitonin gene-­related peptide (CGRP), substance P and bradykinin characterize neurogenic inflammation in CRPS, supposed to be mediated by impaired neuropeptide inactivation and increased receptor availability [44]. Many studies support this association between CRPS and pro-inflammatory neuropeptides as evident by significantly higher levels of CGRP, substance P, and bradykinin in CRPS patients compared to pain-free individuals [45–47]. Other work showed a decrease in levels of CGRP and inflammation following successful treatment of CRPS [45]. Increase in levels of pro-inflammatory cytokines and neuropeptides combined with a decrease in systemic levels of anti-inflammatory cytokines (evident in CPRS patients), plus  the  interplay in mediating localized vasodilation, edema, warmth, erythema and diaphoresis symptoms provide the formula  that is characteristic of this condition [1]. Beyond the central and peripheral mechanisms in the pathogenesis of CRPS, familial CRPS occurrence has been described by several studies, suggesting some sort of genetic influence on the development and maintenance of this condition [48, 49]. Patients with familial CRPS have been reported to have an earlier and more frequent spontaneous CRPS-onset relative to patients with non-familial CRPS [48]. Another study indicated the presence of a threefold increase in risk of developing CRPS in the siblings of patients younger than 50 years with the disorder [49]. These studies point towards the possibility of CRPS being viewed as heritable disorder in certain cases [1]. In other work, associations between certain major histocompatibility complex (MHC) related-alleles and CRPS development have been highlighted

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by several studies [50–54]. The frequency of alleles such as D6S1014*134, D6S1014*137, C1_2_5*204, and C1_3_2*342 were significantly higher in CRPS patients with dystonia compared with controls, while alleles such as D6S1014*140 and C1_3_2*345 were found less frequently in CRPS patients [50]. Similarly, HLA class I alleles such as HLA-B62, and HLA class II alleles including HLA-DQ1, -DQ8, -DR6 and –DR13 were also found to be associated significantly with CRPS [51–54]. In other studies investigating TNF-α promoter gene variations in patients with CRPS, findings of greater association between the TNF-2 allele, yielding an exaggerated inflammatory response due to the production of higher amounts of TNF-α, and warm CRPS have been noted [51]. Lastly, psychological factors have been always implicated in the development of CRPS.  Given its odd symptomology such as pain sensations beyond stimulated nerve distributions, relative unease of affected patients, poorly understood pathophysiology and treatment resistance, CRPS was thought of as purely psychogenic [1]. However, recent advances in uncovering the pathophysiologic mechanisms underlying this condition have given us clues that psychological factors may indeed play a role in its development, albeit indirectly. Increased catecholaminergic activity associated with anxiety, anger, depression and likes of emotional stressors could directly increase CRPS pain intensity (via adrenergic-receptors expression on post-­ traumatic nociceptive fibers), potentially exacerbate the vasomotor signs of CRPS (via adrenergic receptor up regulation), as well as maintain central sensitization (via persistent hyper-excitability of nociceptive neurons at the spinal cord due to pain exacerbation) [1, 55–57]. These premises are supported by findings of greater pain-­ exacerbating effects of emotional distress in CRPS patients, as well as greater CRPS pain-intensity following increased depression levels [58–60]. Furthermore, the association of increased levels of pro-inflammatory cytokine release in response to painful stimuli with catastrophic thinking, along with immune function aberrations associated with psychological stress have been indicated by some studies [61, 62]. Given the previously discussed inflammatory mechanism in the pathogenesis of CRPS, these studies highlight the possible role of interaction between the psychologic and immune factors in the development of this condition. A summary of the interplay of multiple pathophysiological mechanisms fundamental to the development of CRPS is illustrated in Figs. 1 and 2.

Diagnosis Chronic Regional Pain Syndrome presents as an exaggerated response to injury with magnified nociceptive, autonomic and vascular transitions surpassing the anticipated clinical progression of the triggering event often eliciting serious deleterious damage. There are many schools of thought in its diagnosis but not one agreed upon consortium [63]. CRPS-I clinically supports radiating Pain, thermal disparity between affected and contralateral side, pigmented change of skin between affected and contralateral side, propagated edema, limited movement, allodynia and hyperalgesia. Other

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Table 1  Budapest criteria 2003 Criteria 1 Constant pain exaggerated to trigger 2 Symptoms: one reported in three of the total four mentioned on the right 3 Signs: once evaluated, one sign in two or more of the mentioned categories on the right 4 No other diagnosis can explain the patients signs and symptoms

Sensory –

Vasomotor –

Sudomotor –

Motor/ degeneration –

Hyperasthesia; Allodynia

Temperature imbalance; Changes in skin color; Skin color imbalance. Skin temperature imbalance (>1 °C); Changes in skin color; Skin color imbalance. –

Swelling; Sweating changes; Sweating imbalance

Limited range of motion; Motor impairment; Degeneration (skin, hair and nails)

Swelling; Changes in perspiration; Perspiration imbalance

Limited range of motion; Motor impairment (weakness, tremor, dystonia); Degeneration (skin, hair and nails)

–

–

Hyperalgesia (pinprick); Allodynia (light touch or temperature); Deep somatic pressure; Joint movement –

diagnostic criteria included are pain of neuropathic origin, vasomotor fluctuation, or perspiration, joint contracture, swelling, and limitation in movement [64]. Quantitative Sensory Testing (QST) is a valid and reliable method that is utilized to decide the pain threshold as well as sensory component of varying thermal degrees, and fluctuating reverberations. A study was conducted with QST on both CRPS-I and CRPS-II patients displayed increased thermal, mechanical hyperalgesia, and decreased cold and mechanical allodynia [65]. A CRPS diagnostic consensus was reached in Orlando in 1994 by the International Association for the Study of Pain, the first organization to recognize CRPS as an individual body tailored with 4 conditions as a foundation to place such a diagnosis: (a) Triggering event or a justification for limitation of movement, (b) chronic pain, allodynia and hyperalgesia surpassing the trigger, (c) history of swelling, vascular changes, aberrant sudomotor function in afflicted area, (d) no justification or cause for this condition evident. CRPS was additionally characterized into CRPS Type I (absence of nerve injury), and CRPS Type II (evidence of nerve injury). However, this was an ambiguous diagnostic criteria for CRPS [66]. Hence, in 2003, stricter criteria for CRPS diagnosis were introduced, recruiting descriptive components to the sensory, vasomotor, sudomotor and motor features necessary to make a diagnosis of CRPS. It’s known as the Budapest Criteria 2003, and is shown in Table 1 [67]. However, the Budapest criteria once employed led to 15% of those formerly diagnosed by the Orlando criteria to be deprived of the CRPS diagnosis. Therefore, in such cases, a new category of CRPS was generated known as CRPS-NOS (Not otherwise Specified). That is, this diagnosis is granted to such

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patients who do not fulfill the Budapest Criteria yet their signs and symptoms fail to fulfill any other diagnosis [68]. To reach a clinical diagnosis of CRPS, several benchmarks are required including a medical history, physical evaluation, bone scan, tests for the sympathetic nervous system, and thermography which checks skin temperature, blood flow, and amount of perspiration. In addition, radiographic examination indicative of mineral loss, magnetic resonance imaging can elaborate changes in the tissues [67].

Treatment Treatment of CRPS varies according to the type (CRPS I or II) and stage of the condition (acute or chronic). CRPS I follows an injury and the CRPS-II involves a confirmed neuropathic pathology, while acute CRPS frequently implicates a painful, warm and inflamed afflicted limb and chronic CRPS involves exclusively pain as the major culprit [69]. Incessant unresolved CRPS is more challenging to treat due to its chronicity, with a longer duration causing a cascade of relentless pain, frailness, rigidity, and osteopenia [70]. Initially, non-pharmacologic therapeutic approach is used, in the form of physical and occupational therapy for limitation of movement. The aim is for the CRPS patient to resume normal function and daily activities [71]. Pharmacological therapeutic approach is custom directed to the signs and symptoms, for example non-steroidal anti-inflammatory drugs (NSAIDs) or steroids are used for inflammation. One study showed somewhat promising therapeutic effects of oral prednisone in 2 of a total of 31 patients diagnosed with refractory CRPS where pain intensity was reduced to baseline. However, there might be a disparity in the efficacy to the nature of the CRPS as it is refractory to other therapeutic modalities. This highlights the need for more studies with higher level of evidence [72]. In other work, a wonderful response to high doses of oral glucocorticoids (100 mg of prednisolone), exactly tapered down to 25 mg every 4 days, was demonstrated. However, long standing or more aggressive cases of CRPS may require higher doses, reaching up to a 1000 mg of methylprednisolone [73]. Most promising of treatments are ketamine infusions, targeting N-Methyl-D-­ Aspartate (NMDA) receptors which modulates and helped pain, quality of life but not Physical central system sensitization by opposing pro inflammatory cytokines. One study was conducted on 20 CRPS subjects with longstanding spreading CRPS where treatment involved anesthetic doses of ketamine [74]. Significant rates of remission and improved overall quality of life was indicated. However, the treatment did not help with mobility in affected limb [74]. Another successful treatment protocol demonstrated in a case study involved the anesthetic ketamine together with the benzodiazepine, midazolam (versed) for 6 days, in a patient with CRPS type I that was spreading and severe in intensity [75]. The patient was refractive to conventional treatment and this cocktail of ketamine and midazolam alleviated and resolved his symptoms long enough to encompass 8  years in remission [75]. In other words, a 4 day ketamine infusion of 30 mg per hour for 4 days was shown to

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cause pain reduction for up to 3 months [76]. Another study showed 50% reduction in pain intensity of those with CRPS with 5% Lidocaine Pacth [77]. Regarding CRPS-patients with bone loss, bone metabolism is targeted via calcitonin and bisphosphonates. There is a pearl of evidence on the efficacy of bisphosphonates working by opposing the enhanced osteoclastic activity in CRPS subjects, along with opposing inflammatory trauma [78]. Oral alendronate (40 mg) a day for 8 weeks or 7.5 mg intravenously (IV) for 3 days, clondronate (300 mg) per day as an IV for 10 days, pamindronate as a single dose of 60 mg or neridronate (100 mg) every third day repeated 4 times, are all suggested [79]. A cocktail of anticonvulsive medications such as, pregabalin or gabapentin can be used to treat CRPS-pain, similarly to neuropathic pain. A study involving the latter (gabapentin), revealed only average effects on allodynic pain [80]. Tricyclic antidepressants such as amitriptyline which have a sedating effect can also be used, especially when sleep hygiene is an issue [79]. Opioids are indicated for unremitting pain, decreasing at least 50% of the pain if not more within a fortnight, and should only be considered as on trial, taking into account the risk of opioid induced hyperalgesia. Additionally, CRPS patients might not respond to opioids due to diminished central opioid receptor availability [81, 82]. Sympathetic nerve blocks should not be started unless all other conventional therapeutic modalities have failed. Qualified pain professionals should perform these blocks initially as a trial, should 50% or more of pain alleviation happen to the afflicted limb, then should continue twice a week for a period of 5 weeks [83]. Spinal cord stimulation is an invasive but efficient technique in CRPS-pain modulation as opposed to function [84]. Surprisingly dorsal root ganglia stimulation compared to spinal cord stimulation proved to be exceptional in both reduction of nociception and quality of life [85]. Dimethylsulfoxide (50%) harbors anti-inflammatory properties and is used as a topical ointment three times a day and works by depleting the free radicals of inflammation and ischemia released by the CRPS-affected limb [86]. Mirror therapy is employed by physical therapists to support CRPS patients and aid them in believing that the mirror image of the controlled limb is in fact the affected CRPS limb [87]. “Graded Motor Imagery” is an innovative physical therapy modality where by initially a panoramic view of both affected and control limb are viewed by the patient. Second, the patient is encouraged to imagine mobilization of affected side. Finally, the mirror therapy itself is exercised [88]. A relatively new technique known as “Pain Exposure Physical Therapy” is engaged following patient consent as it involves a considerable amount of pain. It is aimed at overcoming pain and shows promise in returning motor function and improving pain perception. However, lacks valid results [89]. Rigidity in the digits following an absolute fracture of the wrist (shifting of the radius bone from the forearm with visually apparent disfigurement) could be associated with edema and thermal disparities. Such cases, known as Colles fractures, don’t respond well to physical therapy as opposed to a Colles fractures without the

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swelling and thermal changes. The latter, in fact responds well to physical therapeutic modalities [90]. Multidisciplinary approach to CRPS also involves such patients with psychologic and depressive comorbidities who are more challenging to treat. Psychologists address such CRPS with Graded Exposure Treatment. This is initiated via the Psychologist by identification of the Key trigger then the patient is subjected to these situations slowly yet routinely by his/her physiotherapists, Pain is reduced and function is returned [91]. There is controversy as to the beneficial effect of Treatment in CRPS, it should in fact be directed towards symptomatic and rehabilitative therapy [89]. The dispute in Therapeutic approach for CRPS is mainly due patients defying treatment, not responding, and altogether treatment failure. Could it be to the clinicians and practitioners lack of understanding of the neurobiology of the disease, that is the fundamental mechanism. It is of interest to note that another condition poses similar to CRPS occurring more so in Females. postmenopausal, following a surgical procedure, pain basically supersedes the magnitude of the injury such as Painful Peripheral Traumatic Trigeminal Neuropathy, also known as Atypical Odontalgia. They share chronicity, which involves central sensitization. The accepted underlying root culprit is a person’s immunity, auto inflammatory as well as auto immunity. A unique process signals self-immune activity. The former requires inherent immune system to precisely strike the tissue causing inflammation. Whereas the latter, takes advantage of its inherent immunity and directs its flexible immune system at its own self [92]. It is conceivable that they pair together influencing multiple systems and causing ramifications in the nervous, locomotor, circulatory and integumentary system. There needn’t be an infection for the trigger of autoimmunity and/or auto inflammation, both pathognomonic of CRPS [93]. Autoinflammation, whether constant or intermittent, causes pain due to the inflammatory cycle it poses on joint, muscles, and rash similar to the common osteoarthritis and gout [94]. The root cause is an impairment of the inherent immune system. Inherent immunity serves both cellular and humoral response that is non-antigen specific. That is, it’s essentially the first line of defense against foreign bodies, recruiting the integumentary systems langherns cells, and mast cells. It caters to receptors hosting pattern recognition such as Toll-Like receptors, NOD and NALP receptors, and RIC-I receptors. Whenever there’s a foreign body and these are activated, inflammatory mediators are released including cytokines, complement fragments, bradykinin, prostoglandins, amongst others. Cytokines are key in the release of IL-8 and IL-1ß, the latter believed to be the culprit and arbitrator for pain, in this case CRPS related Pain [95]. To accompany the Pain Model, the Inherent Immune System is responsible for stimulation of complement products such as C3a and C5a together aggravating inflammation thus causing pain [96].

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The resultant complement attack leads to formation of Membrane Attack Complex C5b-9 (MAC) which causes neuropathy via its nerve fiber degeneration “Wallerian Degeneration”. MAC in turn switches on ERK1 which is an intracellular signal that manages acute and chronic inflammation [97]. Both Human and animal studies point to autoinflammation as a role player in CRPS. In early stages of CRPS, it presents as an acute condition with the trademark redness, swelling, heat, and pain. Pathognomonic to CRPS is an added ingredient of inflammatory immune factors including mast cells and activated dendritic cells. TNF- alpha, IL-1ß, IL-6 are elevated in CRPS verses controls. These cytokines are normally elevated during injury, and burn for instance in acute conditions, however, their levels are significantly higher in those with CRPS [98]. Even Keratin producing epidermal cells in skin proximal to CRPS sites revealed elevated cytokines TNF-Alpha and IL-6 than the skin on the counter limb along with lower anti-inflammatory cytokines such as IL-10 [99]. Treatment of CRPS via biologic anti TNF-Alpha shows promise by targeting and alleviating the mechanical allodynia caused by the inflammatory cytokine TNF-Alpha [100]. In animal models it was observed that Nerve Growth Factor (NGF), a nociceptive related neurottrophin, is elevated in CRPS.  Treatment targeting this reduced the allodynia, and improved function in the afore mentioned afflicted animal models [101]. • Further animal studies extrapolated that antagonist specific LY303870 opposes Substance P NK1 receptor, helped alleviate pain and erythema associated in both CRPS I and CRPS II models [102] • Both SP and Calcitonin Gene Related Peptide are upregulated in CRPS and are fundamental for significant levels of IL-1ß, TNF-Alpha, and pain related NGF. The reason for their up regulation is thought to be oxidative stress [103]. • A metanalytical study, the first of its kind on the efficacy of Vitamin C 500 mg a day for 50 days Supplementation post wrist fractures in the first year of injury in preventing CRPS-I, was found to decrease incidence of CRPS-I by 50% for case control studies. (43) Vitamin C minimizes edema following burn injuries by minimizing the amplified vascular porosity likely to result from the thermal injury. Vitamin C is also known as a potent Reactive Oxygen Species (ROS) Antidote, meaning that ROS during times of trauma becomes energized and this is opposed by the influence of Vitamin C. ROS if not adequately preserved will be catastrophic and essentially mutilating to cell structure. Thus compounding and exacerbating the chances of CRPS-I [104, 105]. N-acetyl cysteine is also shown to reduce allodynia and hyperalgesia and oxidative stress markers [106]. Other cytokines elevated in CRPS found in animal models within the ipsliateral spinal cord tissue adjacent to CRPS site, interestingly IL-6 and CCL2, both responded to opposition from blockade of Substance P NK-1 receptor LY303870 [107]. Treatment by Chemical Sympathectomy: Sympathetic Adrenegric System is responsible for the upregulationIl-6, animal model studies have shown promising evidence

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that Sympathetctomy reduced the deleterious nociceptive role of Il-6 [108]. However, a systematic review expressed only a transient role on allodynia at best [109]. This is also supported by a recently published retrospective observational study, hence we can assume that it is one of the therapeutic treatment modalities used adjunctively for symptomatic pain relief. Botulinium Toxin prevents acetylcholine release from cholinergic nerve endings helping alleviate neurologic movement disorders such as dystonia. Blocking the sympaethtic nerve can be achieved by targeting the sympathetic ganglion and injecting botulinium toxin A for CRPS related pain in the lower extermities known as a Lumbar Sympathetic Block. Botulinium Toxin B had better and longer duration of pain alleviation than Botulinium Toxin A [109]. Most promising of treatments is the evolving field of Transcranial magnetic stimulation (TMS); a non-invasive field of therapy focused at the cortex. Its claim to fame that on condition of constant cortical sessions “Repetitive” there will be modulation in the neural components. Hence counterattack the chronic neuroplastic changes aiding in perception of Pain [110]. Non-invasive vagal stimulation addresses parasympathetic tone and downregulates inflammatory nociceptive mediators, an emerging field of interest. It increases thermal pain threshold, which, in turn, alters the noxious effect of thermal stimulus. The dulling effect on the somatosensory cortex sheds light on this auspicious field of medicine [111]. Innate and adaptive immunity features immune cell contributions from both Mast Cell and Langerhans dendritic cells. On one hand, there is evidence that Mast Cells are found in astounding amounts in CRPS blister fluid causing degranulation. The degranulated dermal mast cells induced by Substance P and NK1 receptor resulting with nociceptive sensitivity [112]. Recent mouse model studies have advocated the use of CD203c as a novel treatment for neoplastic mastocytosis via its antiproliferative directive. Could this be a potential therapeutic modality for CRPS? [113]. On the other hand, an invitro study conducted on CRPS affected limbs and non affected as well as control, shows depleted percentage of mast cells in proximity to nerve fibers in affected CRPS limbs relative to nonaffected limbs and controls. This elaborates the cost of nerves lost in CRPS, has a ripple effect on the signaling and direction of Mast cell flow; impeding their migration towards the remnant severed nerve fiber. Therefore, the lack of communication between nerve fibers and mast cells might be the key instigator to CRPS. Dermal nerve fiber and mast cell density, and proximity of mast cells to nerve fibres in the skin of patients with complex regional pain syndrome [114]. Up-regulated Langerhams cells in skin of CRPS modeled mice, similar to human studies where it was found in abundance. The longer the duration of CPRS, causes a depletion in Langerhams cells [115, 116]. Limited intravenously delivered Immunoglobulins showed promising results [117]. Therapy via Plasma intervention showed similar effects [118]. Autoimmunity plays a role in CRPS via several animal studies. One of which pursued the injection of purified IgG into mice from CRPS affected patients and non

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CRPS sources, resulting in profound hyperalgesia, edema and substance P by the CRPS source of IgG [119]. IgM also plays a role, and it does so by activating the pain arbitrating complement C5a [120] which inturn causes an upregulation of degranulating mast cells. Once C5a is triggered the entire complement system produces MAC leading to neuropathy [121]. There is good authority on the implication of high levels of spinal C5a on central nervous sentistization causing allodynia and hyperalgesia [122]. Treatment targeted to decrease the ripple effect of TNF Alpha, IL-1ß, Il-6 by biologic anti cytokine agents. Others aimed at components such as ant I-CD20 or calicneurin inhibitors [120]. Impressive immunologic therapeutic modalities may be an option in resistant cases of CRPS where more conservative approaches have failed, however, the benefits of the treatment must outweigh the propensity to infections and certain cancers [120]. In conclusion, there have been documented and advanced therapeutic modalities targeted to alleviate the suffering associated with this century long condition. First described in the Great South during the Civil War, “Causalgia” was the first known term introduced in the mid-19th century describing a condition with features of burning following a gunshot injury to integral nerves [123]. Roentgenograms Gs

NMDR

GPCR PGE2

EP–R

PKCe

Ca+2

PKCe

Priming

Fig. 3  Schematic presentation of CRPS treatment algorithm

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discovered by German Physicist in 1895 helped further analyze the over exaggerated pain thus adopting the name of Su’deck’s atrophy. The German physician responsible described this pain as one accompanied by swelling, atrophy and decreased density of the bone in the area of affliction post trauma [124]. Treatment relies on symptomatic alleviation of the condition at the time of visit. Assuring the maintenance of the pain level at reasonable intensities and deciding when to use more complex treatment modalities to keep the pain at bay (Fig. 3).

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Chemotherapeutics That Impair Microtubule Function: Axonopathy and Peripheral Neuropathies Hai Tran and Gail V. W. Johnson

Introduction Chemotherapy Induced Peripheral Neuropathy (CIPN) is a common, often dose-­ limiting, side effects of many traditional and novel chemotherapeutic agents that can present during chemotherapy or in a delayed fashion. CIPN is difficult to diagnose with no standardized methods of assessment or categorization. This has made the study of CIPN, already a very heterogeneous process, all the more challenging. Although many studies have been published on the topic, the pathophysiology and etiology of CIPN remain elusive and treatment options very limited. The physical and functional impact of CIPN can also be profound, is often lasting, and is consequently a common reason for cessation or limitation of chemotherapy. In this chapter, an overview of CIPN will be presented. Subsequently, the focus is on the epidemiology, diagnosis, preventions and treatments of CIPN that is a consequence of the MTAs. CIPN is a common adverse side effect of chemotherapeutic agents. The prevalence of CIPN is agent-specific with the highest-risk, in decreasing prevalence, in patients receiving platinum-derived compounds, taxanes, thalidomide and its analogues, and ixabepilone, an epothilone B analog [1]. Although a CIPN incidence as high as 85% has been reported, [2] a recent systematic review and meta-analysis indicates that CIPN has an approximate aggregate prevalence of 48% with a prevalence as high as 68% after one month of completion of chemotherapy and down to 30% after six month of completion of therapy [3]. Neurotoxicity can occur with a single high-dose or after cumulative exposures [4]. CIPN is a predominantly sensory neuropathy, but can be present as motor, autonomic or as polyneuropathy [5, 6]. H. Tran (*) URMC Strong Memorial Hospital, Department of Anesthesiology and Perioperative Medicine, Rochester, NY, USA G. V. W. Johnson Department of Anesthesiology, University of Rochester, Rochester, NY, USA © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_7

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The manifestations and progression of CIPN are quite variable and can fluctuate from mild to debilitating, and can be transient or evolve into chronic pain with secondary, permanent neural destruction [7]. CIPN can be devitalizing and at times lead to chemotherapeutic dosing reduction or complete discontinuation, which ultimately can affect survival [8]. Further, CIPN can adversely affect the quality of life of cancer survivors [9, 10]. There is paucity of data with regard to the natural progression of CIPN in cancer survivors beyond one year after chemotherapy completion. However, breast- and colon-cancer survivors who received taxane-related or oxaliplatin chemotherapy were still affected by symptoms of CIPN up to two or six years after cessation of treatment, respectively [5, 11]. The relative lack of understanding of CIPN pathophysiology and risk factors poses a significant challenge in developing therapeutic strategies to prevent and treat the condition. Numerous hypotheses have been proposed regarding the mechanisms of taxane- and vinca alkaloid-induced CIPN including: (1) axonal degeneration secondary to the disruption of microtubules and other cytoskeletal alterations, (2) a direct toxic effect of the chemotherapy agents on mitochondria impeding energy supply particularly at the synapse, (3) dysregulation of calcium homeostasis, (4) increased production of pro-inflammatory cytokines (TNFα/IL1β) and/or decreased production of anti-inflammatory cytokines (IL4/10), and (5) changes in expression and function of ion channels (voltage-gated sodium and potassium channels [NaV and KV], and transient receptor potential channels [TRP]) leading to changes in peripheral neuronal excitability [8, 12–18]. Unfortunately, to date therapies based on the proposed hypotheses have not yet yielded any clinically useful interventions [9]. Nonetheless, some progress is being made. For example, it is known that the incidence of CIPN with eribulin mesylate is significantly lower when compared to paclitaxel, a taxane, at equivalent maximum tolerated doses [19]. The precise reasons for these differences have not been fully elucidated, however there is data using animal models showing that the effects of eribulin are only in the axon, and not in the cell bodies of the dorsal root ganglion (DRG) neurons, and that the drug leads to a stable axonal microtubule network which appears to compensate for the toxic anticancer effects of the drug. In contrast, paclitaxel had significant effects in all DRG neuronal compartments and resulted in significantly greater axonal degeneration [20, 21].

Incidence Seretny et al. conducted the first meta-analysis of CIPN in 2014 and concluded from 31 studies involving 4179 patients, that the prevalence of CIPN was 68.1% within one month after chemotherapy, 60.0% at 3 months, and 30.0% at 6 months or later. Meta-regression analysis showed that the specific chemotherapy agent type used accounted for 32% of the heterogeneity seen between studies while time of assessment accounted for 36% [3]. Brozou et al. reported in a systematic review of Platin-­ induced Peripheral Neuropathy (PIPN) that 45.8% of patients experienced painful symptoms with their neuropathy [22].

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Risk Factors As with other forms of neuropathy, existing neurologic injury may predispose a patient to developing CIPN.  Patients receiving certain medications, particularly platins, have higher incidence of CIPN. Other risk factors, however, remain unclear but may include: female gender, higher baseline pain scores, and obesity [23]. At the genetic level, efforts have focused upon identifying genetic risk factors, however investigations into numerous genes with plausible associations with the development of CIPN such as AGXT, GSTP1, and CYP2C8 have not identified any correlations [24]. Nonetheless, there has been success. For example, specific genetic mutations have been identified that have profound effects on the severity of and increase risk for CIPN associated with vincristine therapy. Individuals with Charcot-­Marie-­Tooth disease type 1A (CMT1A) and ERG2 gene mutations are highly susceptible and more sensitive to vincristine, respectively [25, 26]. Polymorphism of the CEP72 gene that encodes the centrosomal protein of 72 kDa is also correlated with an increase in both risk and severity of vincristineinduced CIPN [27]. There are also non-genetic risk factors that can contribute to the development of CIPN and need to be considered prior to the initiation of treatment with a specific chemotherapeutic agent. For example, prior exposure to another chemotherapeutic agent, preexisting peripheral neuropathy from conditions such as diabetes mellitus, renal insufficiency with reduced creatinine clearance, a history of smoking, paraneoplastic antibodies, and cancer-associated neuropathy [28–31].

Mechanism of Injury Microtubule-targeting agents (MTAs) are used to treat many different forms of cancer. MTAs impair microtubule dynamics which disrupts cell division and cellular integrity and transport processes. Disruption of these processes can result in tumor cell death [32]. Unfortunately, MTAs also impair microtubule function in non-tumor cells, and in particular peripheral neurons, and thus often result in significant side effects. One of the most prominent and debilitating side effect of MTAs is chemotherapy-­induced peripheral neuropathy (CIPN) which is primarily due to a disruption of axonal function (axonopathy). The majority of patients treated with MTAs develop CIPN within the first month of treatment and progress as treatment continues. CIPN usually presents with neuropathic pain, numbness and tingling in the distal extremities as well as a hypersensitivity to mechanical or thermal stimuli. After cessation of treatments, symptoms often resolve in a short period of time, however chronic neuropathic pain can also be an outcome [33, 34]. In this chapter we will begin with a review of the basic cell biology of microtubules with an emphasis on their role in cell division and maintaining neuronal function. The three major classes of MTAs will be presented followed by a discussion of the induction of axonopathy by MTAs as a major contributing factor to peripheral neuropathies and why patients are differentially sensitive to the adverse outcomes

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of MTAs. We will conclude this chapter with therapeutic interventions that have been tried to prevent or attenuate CIPNs.

Basic Cell Biology of Microtubules With few exceptions, microtubules are found in the cytoplasm of all eukaryotic cells. All microtubules are 24–25 nm in diameter but vary dramatically in length. All microtubules are composed of dimers of α and β tubulin, and when not polymerized as microtubules exist as heterodimers. The α/β dimers are 8 nm in length and are arranged head to tail so that microtubules have a defined polarity, i.e., the two ends of the microtubules are not equivalent. Tubulin dimers are usually arranged in 13 longitudinal rows or protofilaments, which surround a hollow appearing center. Further, microtubules are dynamic structures; assembling and disassembling as needed to support the function of the cell. In vitro the addition and removal of α/β tubulin dimers occurs at both ends of the microtubules (referred to as plus (+) and minus (−) ends), however the on/off rate of the dimers is significantly faster at the “+” end compared to the “−” end; i.e., the “+” end is more dynamic. Indeed, in the cell tubulin dimers are added or removed almost exclusively from the “+” end of the microtubule. Both α and β tubulin are GTP binding proteins and GTP binding is required for polymerization into microtubules. GTP binding by α tubulin is extremely tight and is “non-exchangeable”. GTP binding to β tubulin is exchangeable and when the dimer is incorporated into a microtubule the intrinsic GTPase activity results in hydrolyses of GTP to GDP on β tubulin. However, exchange of GTP for GDP on β tubulin does not take place when the tubulin is polymerized into the microtubule, it only occurs when tubulin is in the free dimeric form [35]. Microtubules exhibit a novel behavior called “dynamic instability” whereby an individual microtubule exists in persistent phases of elongation or rapid shortening by addition or loss of tubulin dimers, respectively, primarily from the “+” end” of microtubule, with abrupt transitions (catastrophe or rescue) between the phases. A primary regulator of this behavior is GTP and the GTPase activity of β tubulin. Tubulin must have GTP bound in order to be incorporated into a microtubule and once it is polymerized the GTP can be hydrolyzed to GDP. The dissociation rate of tubulin-GTP is much slower than tubulin-GDP and therefore as long as the addition rate of tubulin-GTP is greater than the rate of hydrolysis of GTP to GDP the microtubules will maintain a “GTP cap” and be more likely to be in an elongation phase. However, when the rate of GTP hydrolysis exceeds the rate of addition of tubulin-­ GTP and thus the terminal dimer has GDP bound the microtubule will transition into a shrinkage phase until they are recapped by a tubulin-GTP. It also needs to be noted that although GTP is a primary regulator, it is not the only factor determining the state of microtubules. For example, the presence of microtubule associated proteins (MAPs) and microtubule severing enzymes also play a role in mediating microtubule dynamics. Indeed, loss of the tubulin-GTP cap has been shown to be necessary but not sufficient to initiate the rapid shortening phase. For a recent review on microtubule structure and dynamics see [36].

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 he Role of Microtubules in Mitosis: Rationale for Microtubule T Targeting Agents (MTAs) as a Cancer Therapy In non-dividing cells interphase microtubules exhibit a relatively low level of instability. However, when a cell is preparing to undergo mitosis the interphase microtubules catastrophically disassemble followed by the assembly of spindle microtubules that are significantly more dynamic than interphase microtubules [37, 38]. Spindle microtubules play an indispensable role in facilitating the separation of the sister chromatids and localization to each of the daughter cells. The success of the process requires the microtubule to be highly dynamic with different populations of microtubules exhibiting distinct behaviors. Although all the microtubules of the spindle have their “−” ends at one of the two spindle poles (centrosomes), they play different roles during mitosis. Kinetochore microtubules attach to the kinetochore which is a protein complex at the centromere of a chromosome with their “+” end, while polar microtubules extend from each centrosome towards the spindle midzone and overlap, with microtubule motors facilitating their interactions. Astral microtubules project away from the midline towards the cell membrane and are required for the correct positioning of the mitotic spindle. During metaphase the kinetochore microtubules facilitate the positioning of the chromosomes along the spindle midzone. A kinetochore microtubule must attach to each kinetochore on the chromosome, and each chromosome must have its kinetochore bound by a microtubule from each pole. If this does not occur the cell will not transition to anaphase and this failure will eventually result in the cell undergoing apoptosis (programmed cell death). Once all the chromosomes are at the midzone and appropriately interacting with the kinetochore microtubules, there is an abrupt transition into anaphase with synchronous splitting of each chromosome into sister chromatids each with a kinetochore. The kinetochore microtubules undergo catastrophic disassembly resulting in shortening of the microtubules and movement of each chromatid to an opposite spindle pole. Simultaneously the polar microtubules elongate and, concurrent with the action of the microtubule motors, facilitate the separation of the poles. In telophase, the chromatids arrive at each spindle pole and the kinetochore microtubules completely disassemble prior to cytokinesis and reformation of interphase microtubules in the daughter cells. The fact that coordinated microtubule dynamic is necessary for mitosis and cell survival, drugs that suppress the dynamic nature of microtubules arrest cell division and result in cell death, and thus have been used effectively as chemotherapeutic agents. The different classes of microtubule targeting agents will be described below in section (5).

 icrotubules in Neurons and Their Indispensable and Unique M Role in Axons Neurons are post-mitotic cells; nonetheless microtubules play an indispensable role in their structure and function. Neurons are highly asymmetric cells with their axons being significantly greater in length than their cell bodies. In the peripheral nervous system, axons can reach up to a meter in length which is extraordinary given the size

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of the neuronal cell body. Microtubules and microtubule motors play an essential role in the maintenance and functioning of axons. In addition to maintaining the structure and integrity of axons, microtubules are essential for the movement of vesicles, organelles, proteins and other cargoes to the synaptic terminal and back from the synapse to cell body, which is required for the neuron to function normally. Although neurons are not dividing cells, they are susceptible to the effects of MTAs and this often results in serious complications which often limits the use of these chemotherapeutics as a cancer therapy [39]. Although, it is clear that MTAs often induce axonal degeneration and peripheral neuropathies, the mechanisms underlying these drug-induced processes have not been clearly delineated which prevents the development of intervention therapies to attenuate these unwanted side effects. In the sections below the different classes of MTAs are presented with a discussion of their mechanisms of action that make them useful as chemotherapeutics, as well as their potentially debilitating side effects.

Review of Microtubule Targeted Agents (MTA) Microtubule Stabilizers Microtubule stabilizers are MTAs that are used as chemotherapeutics for the treatment of various cancers. Taxanes are microtubule stabilizers that have been used extensively as a chemotherapeutic; and, more recently, epothilones are also being used. Taxanes are diterpenes, two of which, Paclitaxel (Taxol) and docetaxel (Taxotere) are commonly used as chemotherapy agents. Paclitaxel stabilizes microtubules by tightly binding to the β subunit of tubulin on the tubulin lumen side. This strengthens lateral contacts between tubulin subunits and stabilizes the polymerized structure by suppressing microtubule depolymerization and dynamic instability [40–42]. Epothilones act in a similar but not identical manner to taxanes to stabilize microtubules. Epothilones compete with paclitaxel for binding to microtubules and also suppress microtubule instability [43]. Dynamic instability of microtubules is crucial for mitosis. Stabilization of microtubules prevents the proper formation and function of the mitotic spindle which leads to arrest at the G2/M phase of the cell cycle and presumably death of cancer cells [43]. It is assumed that this is the primary mechanism of action by which these microtubule stabilizers slow tumor growth and/or cause tumor regression; however both taxanes and epothilones likely have other targets that might not only contribute to their usefulness as a chemotherapeutics, but also be a factor in their unwanted side effect of inducing peripheral neuropathies [44–46]. Microtubule Destabilizers Vinca alkaloids and eribulin are the two primary classes of chemotherapeutics classified as microtubule destabilizers. Vinca alkaloids bind to β tubulin while it is on the end of a microtubule at a site distinct from that of the taxanes. Tubulin that is bound by a vinca alkaloid cannot be incorporated in the lattice of the microtubule and results in a suppression of dynamic instability and arrest of mitotic cells

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in metaphase. Interestingly, when vinca alkaloids are bound to microtubule “+” ends they become splayed, indicating that the binding to β tubulin is at interfaces between α/β tubulin heterodimers, thus deforming individual protofilaments from linearity [47]. At low concentrations vinca alkaloids do not cause microtubule depolymerization [48, 49]. Vinca alkaloids were originally classified as microtubule destabilizers as the mechanism of action was thought to involve microtubule depolymerization, inhibition of microtubule polymerization and the formation of paracrystalline tubulin-­ vinca alkaloid arrays. However, these outcomes only occurred at high concentrations; [48, 50] of tubulin assembly, while exhibiting quantitatively different tubulin binding properties to the classic vinca alkaloids [51]. It is likely that the suppression of microtubule dynamics that occurs at much lower concentrations is more likely to be their main mode of action as a chemotherapeutic. Eribulin is an MTA with a unique mode of action as it only inhibits the growth phase of microtubules. Eribulin exhibits a high affinity for microtubule “+” ends and a lower affinity for soluble tubulin. Eribulin binds to the β tubulin subunit, which appears to upset the normal equilibrium between dynamic microtubules and soluble tubulin, resulting in a net depolymerization of microtubules despite the evidence that these effects are rooted in eribulin’s inhibition of microtubule growth. In contrast to vinca alkaloids, eribulin binds to open β tubulin at microtubule “+” ends, thus blocking microtubule polymerization without impacting shortening or protofilament linearity, or causing end splaying. Interestingly, the antimitotic effects of eribulin are functionally irreversible at the cellular level, unlike those of paclitaxel or the vinca alkaloids [47]. Although vinca alkaloids and erbulin differentially impact microtubule function, both are used as chemotherapeutics and peripheral neuropathies are a common side effect [29–31].

Assessment and Diagnosis A major obstacle in the diagnosis and treatment of CIPN is the lack of consensus on a universal, standardized method for assessing CIPN that can be uniformly implemented across treatment centers. Assessment methods can be subjective, objective or both. Subjective methods include the popular National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading scale and the self-­ reported outcome measures. A major advantage of the NCI-CTCAE is that it can be quickly and easily performed by healthcare professionals based upon symptoms related to neuropathy. However, a significant drawback is the fact that it is subjective and cannot detail the severity, the type of neuropathy, nor the location being affected [7]. There are also several self-reported outcome measures that are used to assess CIPN.  Two popular assessments are the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire and the QLQ-CIPN20 questionnaire created by Postma and coworkers based on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 (QLQ-30) [52, 53].

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There are two objective assessment methods, the typical neurological examination performed by a professional to determine neurologic deficits, and an invasive nerve conduction study, which has significant limitations. Nerve conduction studies are invasive, painful and cannot detect defects in small nerve fibers, which are principally affected by CIPN [7]. Therefore, this measure has very limited usefulness in identifying and assessing CIPN. Combinations of both subjective and objective scales also exist. The Total Neuropathy Score (TNS) includes provider subjective assessment of signs and symptoms; and an invasive measure of sural and peroneal nerve conduction studies [54]. The disadvantage of TNS is that it is complex and time consuming. Naturally, to minimize the complexity, there are modified versions of TNS that only use the provider’s subjective assessment of signs and symptoms. These are the TNS-clinical (TNSc) scale; and one that omits the quantitative sensory testing, the TNS-reduced (TNSr) scale [55]. These modified scales are more sensitive in detecting and grading the severity of the symptoms of CIPN than the NCI-CTCEA [56]. For now, there is no specific recommendation among the variety of assessment methods available. It seems that an assessment tool that combines both subjective and objective measurement is likely to be more accurate in diagnosing and grading of the severity of CIPN [55]. Additional work is needed in revising existing methods and evaluating their effectiveness before a universal recommendation can be made.

Preventable Measures to the Development of CIPN There is significant overlap between prevention and treatment of CIPN. Preventions avert the development of or minimize the full extent of the clinical manifestation of CIPN before neuronal injury, temporary or permanent, occurs. Treatments alleviate the clinical expressions of CIPN after diagnosis. Often, compounds that have been demonstrated to be effective in animal models of CIPN or in another form of neuropathy, i.e. diabetic peripheral neuropathy, are used in studies to dually prevent the development of and to treat the symptoms of CIPN.  Therefore, the information available could not be fully separated into prevention or treatment. However, for the ease of understanding, it is logical to segregate the available literature into prevention and treatment. CIPN can significantly reduce the quality of life; measures that prevent or at least reduce the severity of the symptoms of CIPN are needed. Unfortunately, since it is likely that, multiple pathways lead to the development of CIPN and the specific mechanisms have not been clearly elucidated, measures to prevent the development of CIPN have remained elusive. For example, in 2014, the American Society of Clinical Oncology (ASCO) published an analysis of the preventive therapies for CIPN based on the results from a systematic review of 42 randomized controlled trials evaluating 18 widely used agents. This analysis showed that there were no agents or group of agents that had demonstrated consistent, meaningful clinical benefit in the prevention of CIPN [57]. Of importance and relating to chemotherapeutic agents that impair microtubule functions, specifically taxane-induced CIPN,

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two agents that can reduce oxidative stress were tested. In a small cohort of patients acetyl-L-carnitine (ALC) was reported to be beneficial in the reduction of the severity of neuropathy and improvement in the symptoms of sensory and motor neuropathy, however in a large randomized controlled trial it was found to actually increase CIPN [58, 59]. Similarly, glutathione demonstrated no benefits in mitigating the symptoms of taxane-induced CIPN [60]. A 2016 summary of the outcomes of all the CIPN trials sponsored by the National Cancer Institute (NCI), which included some of the studies referenced in the ASCO’s guideline, came to the same conclusions, i.e., there are currently no effective interventions for the preventions and/or treatment of CIPN [61]. Given the need for measures that prevent CIPN, investigations continue. Many of the interventions being tested are commercially available drugs, but most of the studies have utilized animal models and have not been extended to human patients. Nonetheless these studies provide important information about possible therapeutic targets and therefore the results from several recent key studies are presented here. In a rat model, losartan, an antagonist for the angiotensin II type 1 receptor (AT1R), was tested for its analgesic effect on paclitaxel-induced peripheral neuropathy. In this study it was found that single or multiple injections of losartan ameliorated the symptoms and delayed the manifestation of paclitaxel-induced CIPN by suppressing the expression of inflammatory cytokines interleukin-1beta (IL1β) and tumor necrosis factor-alpha (TFNα) in DRG neurons [62]. These results are encouraging but studies need to be extended in to human patients. Along these same lines, other drugs that suppress the production of neuroexcitatory and proinflammatory cytokines IL1β and TFNα and/or promote the production of anti-inflammatory cytokines IL4/10  in the DRG might prevent or ameliorate the symptoms of CIPN. Peroxynitrite regulates spinal glia-derived pro- and anti-inflammatory cytokines, favoring the production of the former in the DRG.  In a rat model orally administered peroxynitrite (PN) decomposition catalysts (PNDCs) SRI6 and SRI110 not only prevented but also reversed paclitaxel induced CIPN without interfering with the chemotherapeutic effects of paclitaxel. By blocking the formation of peroxynitrite, proinflammatory cytokines production was inhibited and anti-­ inflammatory cytokines production increased [18]. In a murine model study, three mitogen activated protein kinase (MAPK) inhibitors, two MEK1 and MEK2 inhibitors PD98059 and U0126, and a p38 inhibitor SB203580 prevented but did not reverse paclitaxel-induced behavioral hypersensitivity by blocking the activation of nuclear factor-kappa B (NF-κB) and, as a result, the expression of downstream genes [63]. Extending these studies, Meng et al. used a mouse model to show that duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), improved the symptoms of CIPN and had the potential to prevent or partially ameliorate the development of CIPN by inhibiting the activation of p38, thus preventing the activation and nuclear translocation of NF-κB, which has been implicated in the development of oxaliplatin and paclitaxel-induced CIPN. Blocking p38 activation attenuated the inflammatory response by suppressing the expression of IL-6 and TNFα in the DRG, and upregulated the expression of nerve growth factor (NGF), which supports neuronal health [64].

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Recent studies have described so-called “silent agonists” of the α7 nicotinic acetylcholine receptor (nAChR) [65] which can elicit significant dose- and time-­ dependent antinociceptive actions in chemically-induced acute pain and chronic neuropathic pain in animal models [66]. Encouragingly, the α7 nAChR silent agonist, R-47, was able to prevent and reversed paclitaxel-induced CIPN in a mouse model without interfering with the anticancer therapeutic effect of paclitaxel [67]. Further studies are needed to determine if α7 nAChR silent agonists are effective at ameliorating CIPN in humans. There is also data suggesting that metformin, an AMP-activated protein kinase (AMPK) activator has the potential to prevent the development of CIPN. Co-administration of metformin with paclitaxel attenuated mechanical allodynia in a mouse model, although the underlying mechanisms were not addressed [68]. Another study indicated that metformin has the potential to prevent the development of CIPN by attenuating the expression of the transcription factor hypoxia-­ inducible factor 1 alpha (HIF1α) in the DRG of a mouse model, although it did not alleviate the post-treatment symptoms [68]. In addition to the studies in animal models, there have been a limited number of small studies in human patients. For example, in a recent small cohort study it was reported that breast cancer patients who received gabapentin with paclitaxel chemotherapy had a lower rate of second and third grade neuropathy and significantly lower changes in nerve conduction velocity (NCV) of sural and peroneal nerves compared to patients that only received the paclitaxel [36]. Further, a recent systematic review and meta-analysis of studies that used traditional Chinese medicines to promote blood circulation and dredging collaterals to remove meridian obstruction as a method to prevent and ameliorate the symptoms of CIPN was published, with two of the twenty studies included had paclitaxel as the antineoplastic agent. These analyses indicated that traditional medicines have shown promising results in both preventing and treating the symptoms of CIPN but additional studies are needed [38].

Treatments of the Symptoms of CIPN A variety of treatments have been employed for the treatment of the symptoms of CIPN.  These include antiepileptics, anti-spasmodics, antidepressants, SNRI’s, NMDA receptor antagonist, strong opioids, local anesthetics such as lidocaine patch, nonsteroidal anti-inflammatory drugs and acetaminophen, nontraditional modalities (capsaicin, cannabinoids, acupuncture, and Scrambler therapy); and a plethora of adjuvant therapeutics. However, as of yet there are no established, efficacious treatments for CIPN. To date, trials that have evaluated various agents and combinations of agents have shown limited success. Antiepileptic, antidepressants and SNRI’s have been widely evaluated as the treatments of CIPN because they have been demonstrated to be useful in other forms of neuropathy. The gabapentinoids play a major role in the management of many neuropathic syndromes. Several studies have suggested that gabapentin may be beneficial in

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CIPN and may help prevent higher grade neuropathy after paclitaxel [69]. However in a randomized, double-blind, placebo-controlled crossover trial involving 115 patients who had received various chemotherapeutic agents, there was no significant difference in improvement seen in the patients who received gabapentin vs placebo (average change in pain was 20–30% across both groups) [70]. Lamotrigine, in a very similar study conducted by the same group, was also found to confer no significant benefit [70]. Antispasmodics (including alpha 2 agonist medications such as dexmedetomidine, clonidine and tizanidine, or 5HT2 antagonists such as cyclobenzaprine) are commonly used in chronic pain, and alpha 2 agonists in particular have been studied in the setting of diabetic neuropathy, there are no studies to indicate their use in CIPN. Studies of antidepressants amitriptyline and nortriptyline [71, 72] and antiepileptics gabapentin and lamotrigine [70, 73] all demonstrated no efficacy in the treatment of CIPN.  Durand et  al. found that venlafaxine, a SNRI, provided relief of recurrent acute neurotoxicity and decreased the incidence of cumulative permanent neurosensory toxicity from CIPN but the trial was limited to patients with oxaliplatin-­induced CIPN [74]. A Phase III clinical trial was conducted with duloxetine in patients who exhibited symptoms of CIPN from paclitaxel or oxaliplatin [75]. Patients with oxaliplatin-induced CIPN experienced a greater mean reduction between 30% to 50% in pain compared to placebo. Patients with paclitaxel induced CIPN demonstrated no significant benefit with duloxetine therapy. Despite the paucity of high-quality consistent data, duloxetine is the only agent that the ASCO recommends for the treatment of CIPN. This is a “moderate” recommendation [55]. Attempts have been made using a combination of agents to target multiple pathways of CIPN. For example, treatment of patients with a topical mixture of baclofen, amitriptyline, and ketamine (BAK) resulted in modest success in terms of improvement of the sensory and motor neuropathy [76]. It should be noted that a study of topical administration of amitriptyline and ketamine, but no baclofen, showed no significant improvement in the symptoms of CIPN [77]. Nerve injury leads to increased inflammation and upregulation of cyclooxygenase-­2, therefore NSAIDs have been utilized in the treatment of CIPN and other neuropathies [78]. While commonly used to decrease overall pain burden, there is no evidence from human studies to show that NSAIDs such as ibuprofen significantly improve CIPN. Several animal studies, however, do suggest a potential protective role of COX inhibitors in reducing experimentally induced (chemotherapy or mechanical) nerve injury as evidenced by changes in prostaglandin levels [78], improved nerve conduction studies [79] as well as a variety of behavioral measures including allodynia and hyperalgesia – two common manifestations of neuropathic pain in humans [78, 79]. This suggests that there may be some utility to the use of NSAIDs as a protective treatment during or prior to chemotherapy administration; however, this must be further borne out in human research before it can be definitively advised. Opioids are not typically favored in the treatment of neuropathic pain due to their side effect profile, risk of habit formation, and tolerance, and few human studies support their use in CIPN [80, 81]. They can, however, be considered for the

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treatment of acute flares of pain which cancer patients often experience, as temporizing medications while achieving adequate titration of other medications [81], or in end-­of-­life care. Nontraditional, alternative modalities including concurrent infusion of calcium and magnesium with the chemotherapeutic agent; capsaicin, acupuncture, and Scrambler therapy have been evaluated as treatments for CIPN.  Based on initial findings and clinical experience, up to 40% of oxaliplatin infusions in the Unites States were given with concurrent calcium and magnesium [82]. Since Loprinzi et al. showed in 2014 in a Phase III randomized, placebo-controlled, double blind trial that there was no therapeutic benefit to this approach [83], it has been largely abandoned. In 2019 a randomized controlled trial with 16 patients evaluated the efficacy of topical 8% capsaicin, a compound isolated from chili pepper, for the management of the symptoms of CIPN.  It was reported that the treatment group had significant improvement in pain relief compared to placebo. However, there were no changes in quantitative sensory testing before and after capsaicin treatment [84]. These data suggest that capsaicin may be efficacious in pain relief but additional studies are needed. Along the same lines, a systematic review by Baviera, et al. focused on five studies describing the use of acupuncture to suppress the symptoms of CIPN and improve quality of life. Vincristine, which is an MTA was one out of the four chemotherapeutics used in the five studies. It was reported that all studies showed modest improvement in symptomatology with acupuncture without any significant side effects. There were quality issues associated with those studies, however, and it was recommended that more randomized control trials are needed to assess the efficacy of acupuncture in the management of the symptoms of CIPN [85]. Another systematic review also focused on the use of acupuncture to relieve CIPN symptoms. Only three randomized controlled trials were included in the analysis with one of the three including both taxanes and vinca alkaloids as antineoplastic agents [86]. Interestingly, none of these trials were included in the publication by Baviera, et al. This study supported previous findings that acupuncture appears to improve the symptoms of CIPN and quality of life of patients, but additional studies are needed [86]. A recent clinical trial involving 33 patients with established CIPN found that there were physical and functional improvements and alleviation of sensory symptoms with acupuncture that were statistically significant compared to placebo. Similarly, the authors recommended additional trials to confirm the interesting results [87]. Numerous nonpharmacologic interventions have been suggested in the setting of CIPN, including medicinal herbs [88, 89], multivitamins, acupuncture [86, 90], Scrambler therapy and transcutaneous electrical nerve stimulation (TENS) [91–95] however most have not been shown to be efficacious or are limited in applicability. Exercise appears to confer some benefit in CIPN [96–98] and certainly may help to counter deficits in balance, function, and mood that many cancer patients exhibit. Scrambler therapy, which can be thought of as “white noise” therapy delivered in a similar fashion as TENS may be a promising treatment although evidence at this stage is limited [94, 95] and a randomized sham-controlled trial showed no difference between sham and Scrambler Therapy [93].

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Scrambler therapy was described and developed by Guiseppe Marineo, a biophysicist. Marineo postulated that the chronic pain process can be altered by interfering with afferent pain using electrical stimulation, similar to transcutaneous electrical nerve stimulation (TENS) [99]. In 2016 a systematic review of Scrambler therapy on the management of chronic pain was published. The results of this review indicate that Scrambler therapy appears to provide significant benefits for patient with refractory pain syndrome [99]. There were twenty studies included in the review with most of them having small sample sizes. Of the twenty studies included in the review, only three were studies of Scrambler therapy on patients with CIPN.  Of those three studies, two out of the three reported improvement from 50–53% reduction in pain [100, 101] and one study reported no difference [102]. A fifty patient randomized controlled trial comparing Scrambler therapy to TENS in patients with documented CIPN.  In this study patients who received Scrambler therapy had up to 50% improvement in pain, tingling, and numbness scores, and there were as many as twice the number of patients in the Scrambler therapy group who saw improvement in their symptoms compared to those in the TENS group [103]. However in another a randomized controlled trial comparing Scrambler therapy against sham therapy in patients with CIPN, there was no significant difference in relief between the two groups [104]. Therefore, further studies are clearly required to establish the efficacy of Scrambler therapy in treating CIPN. There is increasing interest in using cannabinoids to treat the symptoms of CIPN [105]. However, the efficacy of these agents remains to be established. There are other complementary therapies such as exercise-based rehabilitation and herbal medicines/phytochemicals for the treatment of CIPN. There is evidence to suggest that exercise-based rehabilitation is beneficial in with CIPN in both better coping of their symptoms and improvement in their quality of life [106, 107]. There is limited evidence regarding the benefits of herbal medicines and phytochemicals in the treatments of the symptoms of CIPN [108].

Summary There is no universally recommended evaluation method for the symptoms and severity of CIPN. Currently, duloxetine and exercise have the greatest amount of supporting evidence. There are no efficacious preventions of the development of or treatments for the symptoms of CIPN. It appears that to successfully prevent CIPN, a combination of agents that target several pathways would be required. Additionally, the results of clinical trials suggest that preventions strategies would need to be administered before, during, and after chemotherapeutic treatment for the therapies to be effective. Similarly, it is likely that controlling the symptoms of CIPN requires a multidisciplinary approach with combination of physical/psychological therapies to improve quality of life and medicines that target the different receptors. Treatments should be tailored to the patients and also to the chemotherapeutic agent(s) that the patients received. It is important, therefore, that research be continued both on the various mechanisms of injury underlying CIPN.

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Diabetic Peripheral Neuropathy Hai Tran and Daryl I. Smith

Introduction Diabetic peripheral neuropathy (DPN) presents one of the greatest on-going challenges to both acute and chronic pain management, yet our understanding of the molecular origins and pathogenesis of this complex disease state is inadequate. This chapter will discuss some of the more conclusive literature regarding DPN. Because of the multifaceted origins of diabetic peripheral neuropathy, this cannot be discussed as a single entity, but we can seek to identify a final common pathway. The vascular supply to peripheral nerves is often overlooked in the natural history of common, well-understood diseases as well as in the management of acute and chronic pain syndromes (Fig.  1). When chronic peripheral neuropathic pain develops, the results can be devastating. There is significant impairment in quality of life (QoL); functioning in the activities of daily living (ADL); and significant loss of productivity. We will examine some of the known pathogenetic origins of DPN, and then discuss the effect of resultant hemodynamic alterations to determine any correlations between these alterations and specific effects upon neural structure and function in the hyperglycemic milieu. Lastly, we proffer some of the data for newer potential treatments of DPN. Peripheral neuropathy (PN) of all types is a relatively rare but well-known degenerative disorder of the peripheral nervous system with an estimated annual incidence of 1.6 per 100,000 and a prevalence of 2.4 percent in the United States [1, 2]. For persons forty years and older, the prevalence is about five-fold higher (11.5 H. Tran URMC Strong Memorial Hospital, Department of Anesthesiology and Perioperative Medicine, Rochester, NY, USA D. I. Smith (*) University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_8

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Sympathetic nerve ganglion

Epineurium

Noradrenergic peptidergic fibers

Perineurium

Endoneurium

Epineural Artery

Transperineural arteriole

Postcapillary venule

Epineural vein

Endoneural capillary

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Fig. 1  Schematic of the vascular supply of peripheral nerves

percent) and 10 times higher in diabetic individuals (21.2 percent) [3]. Among the causes of PN are diabetes mellitus, toxins, alcohol abuse, or paraneoplastic syndromes with diabetes mellitus as the most common cause of PN worldwide. Both sensory and/or motor component (sensorimotor) of the peripheral nervous system (PNS) can be affected. The symptoms, severity and duration of PN depend on the type of nerve affected, sensory, motor or both, the inciting incidence or causative agent, and the length of exposure. Motor neuropathy is characterized by muscular weakness affecting mobility, coordination, and respiratory function. Sensory neuropathy is characterized by pain, numbness, burning sensation, absent or diminished reflexes and sensation to touch. The generalized category DPN is a common neurological manifestation of both Type 1 and Type 2 diabetes. It affects up to 50% of diabetics and there is an even greater incidence in those with subclinical manifestations, i.e., asymptomatic DPN. The PN can involve both motor and sensory nerves and the complexity of the metabolic and vascular factors involved still has not been fully elucidated. The sensory loss is classically described as a “stocking and glove distribution” involving both hands and legs. The underlying pathology causing this neuropathy appears to involve both macro- and microvascular processes. We now know that diabetic neuropathy is not likely one separate or discreet entity but a malady that is the endpoint of a number of different mechanisms that may be enhanced by the hyperglycemic state.

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The problem we encounter as practitioners who must manage the care of patients suffering from DPN and, more specifically, the debilitating pain that results from DPN is that the categorical treatments available for the management of this malady are oft times ineffective. Standard, accepted treatments have included tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, or γ-aminobutyric acid analogues gabapentin and pregabalin. Patients in whom these initial regimen agents are ineffective often receive opioids and topical therapies such as capsaicin as the next line of treatment. Unfortunately, these therapies lack the desired consistent efficacy necessary to instill confidence in either physicians or patients that adequate analgesia can routinely be obtained. The relationship of DPN to regional neural blood flow was described by Dillon et al. when they concluded that slow-healing of neuropathic ulcers were associated with a loss of cholinergic nerve function and that cholinergic stimulation would increase capillary blood flow. They also suggested that improved blood flow to the neural supply of the region may have an overall beneficial effect to the insulted tissue [4]. In 1997, the same group advanced their work to conclude that peripheral blood flow is inversely related to the degree of peripheral neuropathy [5]. These important hemodynamic dependent mechanisms of neural injury now appear to stem from galactose neuropathy and resultant oxidative stress; angiotensin converting enzyme-mediated neuropathy; glycochelates and transition metal mediated neuropathy.

Molecular Mechanisms of Diabetic Neuropathy Galactose Neuropathy and Oxidative Stress As far back as 1984 galactose was implicated as a cause for PN in a murine, diabetic model. Using C14 iodoantipyrine as a radioactive tracer of tissue perfusion, Myers et al. noted a significant decline in nerve blood flow in animals that had ingested galactose for 6 months versus controls. There was a positive correlation between galactose ingestion, endoneurial edema, increased tissue pressure, and ultimate demyelination of nerve fibers. The group also found that Schwann cells showed significant glycogen accumulation in regions in which there was edema. This bolstered the argument that edema, rather than neural hyperactivity in the sorbitol pathway was responsible for the pathological changes in galactosemic neuropathy [6]. Most recently however the sorbitol pathway has returned to the fore as the primary mechanism of glycemic based neural injury. The sorbitol pathway is an alternative to a primary intracellular pathway of glucose metabolism. the polyol pathway. The polyol pathway is dependent upon aldose reductase (AR) which reduces toxic aldehydes in the cell to inactive alcohols. In the hyperglycemic state AR is rendered incapable of dispatching the glycemic burden in the usual fashion and thus transitions to the reduction of glucose to sorbitol. The glucose reduction pathway which generates sorbitol also subsequently oxidizes sorbitol to fructose. The sorbitol branch of the polyol pathway consumes the cofactor NADPH, which is the essential

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Hyperglycemia

Polyol

AGE/RAGE

ROS

Risk factors Hypertension Hyperlipidemia Smoking Insulin resistance

Direct injury PARP PKC MARK

Proinflammatory processes

NF-kB Neurotrophins Cytokines Macrophages

Hypoxia Endoneural microangiopathy

stem cells Ischemia/reperfusion macrophages/ monocytes

Neuropathy

© G. Hintz 2020

Fig. 2  Summary of the known interactive pathways from hyperglycemia to Diabetic Neuropathy (AGE-Advanced Glycation End products, RAGE- Receptor for Advanced Glycation End products, ROS- Reactive Oxygen Species, PARP-Poly(ADP-Ribose) Polymerase, PKC- Protein Kinase C, MAPK- Mitogen Activated Protein Kinase, NF-κB- Nuclear Factor kappa-light-chain enhancer of activated B cells)

cofactor for regenerating the important intracellular antioxidant, reduced glutathione (GSH). Lack of GSH has been shown to induce as well as exacerbate oxidative stress. The result of which includes thickening of the capillary basement membrane in the retina, kidney and muscle [7]. The current thought regarding diabetes-specific microvascular disease in the vasa nervorum includes the following: hyperglycemia causes abnormalities in blood flow and increased vascular permeability (Fig.  2). Early discussions of diabetic neuropathy have emphasized the hyperglycemic insult. The key factors of emphasis are resistance to vasodilators, hypersensitivity to vasoconstrictors and elaboration of permeability factors such as VEGF. The sum of these changes results in edema, ischemia and hypoxia-induced axonal degeneration in peripheral nerves [7]. In 2016, Ozaki, et al. sought to examine the role of hypertension in diabetic neuropathy. They employed a murine model using alloxan-­induced diabetic rats and non-diabetic rats. In both groups blood pressure was maintained above 140 mmHg. While both groups showed endothelial hypertrophy and vessel lumen narrowing, more severe duplication of the basal lamina surrounding the endothelium and pericytes of the endoneurial vessels was reported [8].

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Angiotensin Converting Enzyme (ACE) Mediated Neuropathy The possible link between vasoactivity and ACE in DPN (at least in the murine model) was asserted in a 2007 study by Wang, et al. In this study, serum levels of the adipokine, resistin, was shown to correlate with systolic blood pressure, diastolic blood pressure and serum epithelin levels, and to negatively correlate with the potent vasodilator, nitric oxide [9]. In a more recent study, resistin was shown to induce hypertension and insulin resistance in wild type mice believed to occur by the upregulation of angiotensin (Agt) toll-like receptor 4 expression [10]. In toll-­ like receptor 4 (tlr4)-negative mice or in mice treated with the angiotensin-­converting enzyme inhibitor, perindopril, resistin had no effect. The authors concluded from this that resistin activates the renin-NF angiotensin system via the TLR4/P65-NFKB subunit/Agt pathway which links insulin resistance to hypertension. The higher serum resistin levels in patients with diabetic neuropathy versus diabetics without peripheral neuropathy suggests that resistin may play a role in the pathogenesis of type 2 diabetes and diabetic peripheral neuropathy. The question is also raised regarding whether hypertension secondary to resist in is a causative factor in this neuropathy [10].

Transition Metal Mediated Neuropathy - Glycochelates The role of transition metals was argued in a review article by Qian et al. in 2000. They presented data that heavily glycated proteins, known to accumulate in individuals suffering from diabetes, gain an increased affinity for transition metals such as iron and copper. This affinity results in the accumulation of bound metal by elastin and collagen within the arterial wall. The bound metal is believed to cause the catalytic destruction of endothelium-derived releasing factor (nitric oxide or a nitric oxide derivative). The loss of vasodilatory ability (or chronic vasoconstriction) impairs blood to peripheral nerves with resultant deprivation of oxygen and critical nutrients. The authors cited initial studies that suggest the administration of chelators such as desferrioxamine may prevent or reverse slower peripheral nerve conduction and neuronal blood flow [11].

Therapeutics  enetic Treatment of Hemodynamic Derangements G Caused By DPN Reversal of experimental diabetic neuropathy in a murine model induced by two different techniques was explored by Schratzberger et al. in 2001 [12]. Both streptozotocin- and alloxan- induced diabetes models were employed and nerve blood flow was assessed by laser Doppler imaging or direct detection of a locally administered fluorescent lectin. In both models, intramuscular gene transfer of plasmid

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DNA encoding VEGF-1 or VEGF-2 resulted in increases in vascularity and nerve blood flow to levels found in control animals. The group also reported that constitutive over-expression of both transgenes resulted in restoration of large and small fiber peripheral nerve function as measured by motor and sensory nerve conduction velocities. Similar findings in a lapine model are also reported. There is accumulating evidence, then, that genetic therapy may have a role in the treatment of peripheral neuropathy of diabetic origin. Unlike the observed efficacy of this gene therapy in chemotherapy-induced neuropathy, considerations for induction of related angiogenesis would not be a factor in the decision to institute plasmid DNA therapy; however, a concern for possible retinal angiogenesis and a question of initiating or worsening diabetic retinopathy may be a concern. In this regard, further research is needed first to assess the associated angiogenicity of this treatment in animals and second to establish whether any benefit of this de facto genetic hemodynamic therapy can be extrapolated to a human model [12].

Endothelium-Dependent and Endothelium-Independent Micro-Vasodilatation Therapy The role of endothelium-dependent and endothelium-independent micro-­ vasodilatation and their relationships to neural microcirculatory control was examined in Type I and Type II diabetic patients by Kilo, et al., in 2000 [13]. They used iontophoresis of acetylcholine and nitroprusside in a dose-response technique to elicit C-fiber mediated vasodilation. As expected, endothelium-dependent vasodilation of the cutaneous microcirculation was attenuated in Type II diabetic subjects versus control; however, there was no significant difference between the endothelium-­dependent vasodilation in Type I diabetics versus controls. There was no difference between either diabetic group (Type I or Type II) regarding endothelium-­independent vasodilation. They also found that the C-fiber- mediated axon reflex was impaired in both Type I and Type II diabetics, which the group stated was consistent with a small fiber neuropathy. The study led to the conclusion that endothelial function and nitric oxide play a significant role in the pathogenesis of PN in Type II diabetic patients and that this disease process is the result in part of significant C-fiber impairment. Again, the function of C-fibers, the neural component of peri-neural hemodynamics, and the peri-neural chemical milieu may begin to suggest a common pathway for the perfusion of peripheral nerves and the development of PN.

Angiotensin-Converting Enzyme Inhibitor Therapy Angiotensin-converting enzyme (ACE) inhibition was considered as early as 1998 as playing a role in the treatment of human diabetic neuropathy in a randomized trial. In this work 41 patients with normotension, “mild” diabetic neuropathy and a diagnosis of type I or type II diabetes were placed in the randomized double-blind

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placebo-controlled trial. In which the experimental group was treated with an ACE inhibitor. Assessments of treatment efficacy were made using the endpoint of neuropathic symptoms, deficit scores, vibratory perception threshold, peripheral-nerve electrophysiology, and cardiovascular autonomic function at 6 and 12  months of treatment with the primary endpoint of change in peroneal motor nerve conduction velocity. The study revealed a significant increase in peroneal motor nerve conduction velocity, and M-wave amplitude and sural nerve action potential amplitude. However, vibration-perception threshold, autonomic function and the symptoms of neuropathy and deficit score showed no improvement in either group. Yet the question remained whether reversal of neural functional impairment can lead to symptomatic improvement  [14].  Further clinical study is needed to make this determination.

Free Radicals Scavenging Therapy The oxidative stress and pro-inflammatory processes which contribute to vascular complications including endothelial dysfunction and peripheral neuropathy in diabetes mellitus was examined in a 2006 study by Nangle, et al. [15] In this work, the group administered eugenol  - which is known to have antioxidant and anti-­ inflammatory properties especially in the inhibition of lipid peroxidation - to streptozotocin induced diabetic rats [16]. The group analyzed endoneurial blood flow reduction; gastric fundus maximum nitrergic nerve-mediated relaxation reduction; and maximum endothelium-dependent relaxation reduction in renal artery rings, all in diabetic animals. Eugenol significantly improved or completely reversed each of these reductions but did not affect diabetes-increased sensitivity to phenylephrine-­ mediated contraction. Nevertheless, the study demonstrated that both vascular as well as neural complications of experimental diabetes are improved by the antioxidant/anti-inflammatory agent eugenol. This reinforces the argument for the role of pressure-flow perfusion dependence on the development of oxidative stress-­ related PN. In 2006 Li et al. used a murine model to examine the role of antioxidant therapy in the treatment of diabetic neuropathy. The group looked at the effect of the antioxidant taurine upon sensory nerve conduction velocity, nerve blood flow and sensory threshold in hyperglycemic, Zucker diabetic fatty (ZDF) rats. They ­ ­created experimental groups consisting of lean, non-diabetic rats (ND); ND rats treated with taurine; untreated ZDF diabetic rats (D); and D rats treated with taurine. When compared with controls, deficits in nerve conduction, velocity (both motor and sensory) and nerve blood flow were all reversed by taurine. They concluded that antioxidant therapy may be useful in the treatment of experimental Type II diabetes [17]. The role of peroxynitrite-mediated nitrosative stress in the development of diabetic neuropathy was studied in a murine model by Negi et al. in 2010 [18]. In this work the effect of a combination of peroxynitrite decomposition catalyst (PDC), FeTMPyP [15] and a poly (ADP-ribose) polymerase (PARP) inhibitor, 4-ANI. PARP

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is a nuclear enzyme activated after detection of DNA damage. The rationale for the use of the PARP inhibitor was the role that over activation of this enzyme is believed to play in the development of diabetic neuropathy [19]. The group studied the following endpoints: motor conduction velocity and nerve blood flow for evaluating neural function; malondialdehyde and peroxynitrite levels to detect oxidative stressnitrosative stress; and nicotinamide adenine dinucleotide (NAD+) concentration in sciatic nerve to assess NAD+ overproduction of PARP. Treatment with combination of FeTMPyP and 4-ANI led to improvement in neural function and also attenuated the oxidative-nitrosative stress markers. The combination also reduced the over activation of PARP which was demonstrated by increased levels of NAD+ and by the demonstration of decreased PARP immunopositivity in sciatic nerve microsections. The authors concluded that treatment with a combination of a PDC and a PARP inhibitor attenuates alterations in peripheral nerves in experimental diabetic neuropathy. The role of melatonin in the limiting of oxidative stress-related neural injury was examined by Manasaveena in 2013 [20]. In this work, the group used streptozotocin-­ induced diabetic neuropathy, and oxaliplatin-induced sensory neuropathy murine models. They administered melatonin at doses of 3  mg/kg and 10  mg/kg to the diabetic animals during the 7th and 8th week after diabetes induction. They administered the same doses of melatonin daily to the oxaliplatin treated animals. In both models, melatonin administration significantly increased tail flick latency-an indication of reduced hypersensitivity - when compared to control animals. Motor nerve conduction and nerve blood flow were improved in melatonin treated diabetic animals. Of particular significance and interest, lipid peroxidation was also improved by melatonin in both experimental models. The group speculated that since oxidative stress plays a major role in peripheral neuropathy induced both in the setting of diabetic as well as chemotherapeutic neuropathies, that melatonin might serve as a possible therapeutic choice because of its antioxidant and anti-inflammatory activity. The role of oxidative stress in the process of neurodegenerative diseases and other syndromes was reinforced in an earlier review in 2002 by Srinivasan [21] in which emphasis was placed upon the scavenging of hydroxyl carbonate and various organic radicals; and peroxynitrite and other reactive nitrogen species, in addition to melatonin-medicated stimulation of superoxide dismutase, glutathione peroxidase and glutathione reductase. These works strongly suggest that the impact of oxidative stress upon the function of the neural microvasculature warrants closer study especially with emphasis processes with antioxidant therapy. Another argument for the clinical use of antioxidant therapy was examined by Pop-Busui, et al. in 2013 [22]. The main emphasis of his work was on measures of cardiovascular autonomic neuropathy (CAN) and myocardial blood flow and it was performed as a randomized parallel, placebo-controlled trial. Participants were evaluated by cardiovascular autonomic reflex testing, positron emission tomography, and adenosine stress testing. Markers of oxidative stress included 24  hour urinary-­F2-isoprostanes. Diabetic peripheral neuropathy was evaluated by symptoms, signs, electrophysiology, and intra-epidural nerve fiber density. The study participants underwent a 24-month intervention consisting of antioxidant treatment

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with allopurinol, alpha-lipoic acid and nicotinamide or placebo. They found that in the cohort of type 1diabetes with mild-to-moderate CAN, a combination antioxidant treatment regimen did not prevent progression of CAN; and had no beneficial effects on myocardial perfusion or the measures of diabetic peripheral neuropathy. The need for further clinical study of antioxidant therapy, particularly in the targeting of lipid peroxidation in diabetic peripheral neuropathy as well as in other peripheral neuropathic subtypes is strongly indicated [22]. In 2014 Zhang et  al. evaluated the effect of salvianolic acid on diabetic peripheral neuropathy [23]. They analyzed peripheral electrophysiology, hemodynamics in the peripheral microcirculation, ultrastructure of sciatic nerve observation, and biochemical indicators. They found down regulation of malonyldialdehyde, an end product of lipid peroxidation; advanced glycation end products; total cholesterol; plasma triglycerides; and a decreasing tendency of fructosamine, a glycated protein used as a monitor of glycemic control. In addition they found up regulation of neural nitric oxide synthase (nNOS); brain derived neurotrophic factor which is decreased when blood glucose levels are elevated [24]; and glial cell line-derived neurotrophic factor which has been shown to reverse the neuronal loss caused by a reduction in Akt-mediated survival signaling [25]. They concluded that salvianolic acid could improve peripheral nerve function in type 2 diabetic rats by decreasing oxidative stress damage, improving vascular function in the peripheral microcirculation, and that the drug could promote the expression of neurotrophic factors. The antiatherosclerotic and anti-inflammatory effects of the cannabinoid, rimonabant, on peripheral neuropathies in the diabetic murine model have been examined in a recent work. In this study, diabetes was induced in rats using streptozotocin and the animals were treated for 24 weeks with 10 mg/kg/day rimonabant or placebo. The group then quantified the densities of intraepidermal nerve fibers and total skin capillary length. They also measured current threshold, skin blood flow after treadmill running and TNF-α level in spinal cord tissue or plasma. They found that rimonabant treatment significantly improved the decreased intraepidermal nerve fiber density and alleviated the increased current perception threshold in rimonabant treated versus control diabetic rats. The group reported that the responses were clearly associated with the attenuation of skin capillary loss, increase in skin blood flow, and reduction in tissue TNF-α levels. They concluded that their findings suggested that rimonabant may be beneficial in the treatment of experimental diabetic peripheral neuropathy possibly due to its micro- and macrovascular protective effects [26].

Conclusion Pressure-flow relationships clearly need to be evaluated both in vitro as well as in vivo in human subjects in order to explore possible means of enhancing the treatment of peripheral neuropathy and controlling progression. The evidence of a final common pathway of impaired microvascular reactivity at the vasa nervorum level

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may be of paramount importance as new therapies are sought to limit the effect of this devastating neuropathy.

References 1. Azhary H, Farooq MU, Bhanushali M, Majid A, Kassab MY. Peripheral neuropathy: differential diagnosis and management. Am Fam Physician. 2010;81(7):887–92. PubMed PMID: 20353146. 2. Laughlin RS, Dyck PJ, Melton LJ 3rd, Leibson C, Ransom J, Dyck PJ. Incidence and prevalence of CIDP and the association of diabetes mellitus. Neurology. 2009;73(1):39–45. PubMed PMID: 19564582. Pubmed Central PMCID: 2707109. 3. Cheng YJ, Gregg EW, Kahn HS, Williams DE, De Rekeneire N, Narayan KM.  Peripheral insensate neuropathy--a tall problem for US adults? Am J Epidemiol. 2006;164(9):873–80. PubMed PMID: 16905646. 4. Dillon RS.  Role of cholinergic nervous system in healing neuropathic lesions: preliminary studies and prospective, double-blinded, placebo-controlled studies. Angiology. 1991;42(10):767–78. PubMed PMID: 1952266. Epub 1991/10/01. eng. 5. Dillon RS.  Patient assessment and examples of a method of treatment. Use of the circulator boot in peripheral vascular disease. Angiology. 1997;48(5 Pt 2):S35–58. PubMed PMID: 9158380. Epub 1997/05/01. eng. 6. Myers RR, Powell HC. Galactose neuropathy: impact of chronic endoneurial edema on nerve blood flow. Ann Neurol. 1984;16(5):587–94. PubMed PMID: 6095731. Epub 1984/11/01. eng. 7. Brownlee M.  Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–20. PubMed PMID: 11742414. 8. Ozaki K, Hamano H, Matsuura T, Narama I.  Effect of deoxycorticosterone acetate-salt-­ induced hypertension on diabetic peripheral neuropathy in alloxan-induced diabetic WBN/ Kob rats. J Toxicol Pathol. 2016;29(1):1–6. 9. Wang XH, Wang DQ, Chen SH, Zhang L, Ni YH. The relationship between resistin and the peripheral neuropathy in type 2 diabetes. Nat Med J China. 2007;87(25):1755–7. 10. Jiang Y, Lu L, Hu Y, Li Q, An C, Yu X, Shu L, Chen A, Niu C, Zhou L, Yang Z.  Resistin induces hypertension and insulin resistance in mice via a TLR4-dependent pathway. Sci Rep. 2016;6:22193. PubMed PMID: 26917360. Pubmed Central PMCID: 4768137. 11. Qian M, Eaton JW.  Glycochelates and the etiology of diabetic peripheral neuropathy. Free Radic Biol Med. 2000;28(4):652–6. 12. Schratzberger P, Walter DH, Rittig K, Bahlmann FH, Pola R, Curry C, Silver M, Krainin JG, Weinberg DH, Ropper AH, Isner JM.  Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest. 2001;107(9):1083–92. PubMed PMID: 11342572. Pubmed Central PMCID: PMC209283. Epub 2001/05/09. eng. 13. Kilo S, Berghoff M, Hilz M, Freeman R. Neural and endothelial control of the microcirculation in diabetic peripheral neuropathy. Neurology. 2000;54(6):1246–52. 14. Malik RA, Williamson S, Abbott C, Carrington AL, Iqbal J, Schady W, Boulton AJ. Effect of angiotensin-converting-enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomised double-blind controlled trial. Lancet (London, England). 1998;352(9145):1978–81. PubMed PMID: 9872248. Epub 1999/01/01. eng. 15. Nangle MR, Gibson TM, Cotter MA, Cameron NE. Effects of eugenol on nerve and vascular dysfunction in streptozotocin-diabetic rats. Planta Med. 2006;72(6):494–500. PubMed PMID: 16773532. Epub 2006/06/15. eng. 16. Gulcin I. Antioxidant activity of eugenol: a structure-activity relationship study. J Med Food. 2011;14(9):975–85. PubMed PMID: 21554120.

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Alcoholic Neuropathy Adaora Chima and Daryl I. Smith

Introduction Alcoholic neuropathy appears in approximately 25–66% of defined chronic alcoholics. It is associated with the duration and amount of total lifetime alcohol consumption. Heavy and continuous alcohol drinkers suffer a higher prevalence than more episodic drinkers; and there is a higher incidence in females than in males [1]. This was consistent with in vitro studies that examined the molecular basis of a potential gender difference in the response to neuronal ethanol toxicity in murine models. Following oophorectomy, alcohol ingestion failed to induce hyperalgesia in female rats; while estrogen replacement reinstated alcoholic neuropathy in this same group. Other evidence of gender dimorphism was shown in a comparison of alcoholic neuropathy with complex regional pain syndrome (CRPS). Similarities in the two neuropathies include neurogenic inflammation, central and autonomic nervous system dysregulation and peripheral hyperalgesia. They differ in that ovariectomy does not diminish the produced mechanical hyperalgesia in the murine CRPS model. In the alcoholic neuropathy model, however, ovariectomy tended to protect against alcoholic neuropathy which suggests a pro-nociceptive effect of estrogen on alcoholic neuropathy [2]. Interestingly, protein kinase epsilon (PKCε)- mediated alcohol induced hyperalgesia was significantly attenuated by a PKCε inhibitor to a greater extent in females than in males. The underlying mechanism for this sexual dimorphism is unknown [3, 4].

A. Chima Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA D. I. Smith (*) University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_9

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In the most serious cases of alcoholic neuropathy, the pattern of clinical signs presents in a symmetric distribution of motor deficits. In the less severe cases it presents with sensory derangement but also in a symmetric distribution. The motor deficit includes atrophies and weakness, while the sensory derangement includes early reduction in vibratory sense. On laboratory examination there is decrease in nerve conduction velocity [5]. While  ethanol effects the  supraspinal limb of the central nervous system the symptoms of chronic ethanol abuse are temporally secondary to those of the peripheral nervous system because of the delayed exposure to toxins due to the blood brain barrier [6]. This does not mean that the central nervous system is exempt from chronic ethanol effects. Ethanol intercalates into the cell membrane and thus increases membrane fluidity [7, 8].This may not be the critical event in the neuropathy, however. Instead, specific proteins involved in signal transduction may be more important targets for ethanol. These include ion channels, second messengers, neurotransmitters and their receptors, G-proteins and regulators of gene expression. The next section discusses briefly the role of acute and chronic ethanol exposure upon the supraspinal central nervous system.

Supraspinal Effects of Acute and Chronic Ethanol Exposure GABA Receptors Intoxicating concentrations of ethanol increase chloride flux through GABA-­receptor operated chloride channels. Ethanol is also known to induce changes in calcium channels and this is suspected as a cause of ethanol withdrawal. The intoxicant effect of alcohol as well as the antianxiety and anticonvulsant effects are prevented by the benzodiazepine partial inverse agonist, RO15–4513. The drug also antagonizes the enhancement of GABA-receptor agonist-stimulated chloride flux. For reasons that are relatively clear, this inverse agonist has not been trialed as a potential treatment of alcoholic neuropathy nor should it based upon the fact that GABA is an important inhibitory neurotransmitter and the resultant decrease in its function could conceivably worsen the symptoms of the neuropathy. One study that may be more valuable would be whether clinically indicated use of flumazenil, the most commonly used benzodiazepine antagonist, aggravates the symptoms of alcoholic neuropathy.

Calcium Channels Calcium channel exposure to ethanol  for several days, results in an increase of depolarization-stimulated calcium chloride Ca45 uptake [9, 10]. Despite the removal of this exposure to alcohol, the increase in calcium flux remains for several hours and is associated with an increase in the number of binding sites for dihydropyridine calcium channel antagonists. This in turn promotes neurotransmitter release (Fig. 1). Calcium channel antagonists reduce the incidence of tremors, seizures, and death in alcohol –dependent murine models [9, 11].

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DepolarizationStimulated CaCl Ca45 Uptake

Increased Ca++ Flux

Increases in Neurotransmitter release

Increased Dihydropyridine Ca++ Channel Antagonist

Fig. 1  Summary of the effect of prolonged (several days) ethanol exposure upon calcium channel function in a murine model [9, 10]

Excitatory Amino Acids Ethanol inhibits NMDA-receptor dependent neurotransmitter release, cGMP production, and from the perspective of chronification of pain, the generation of excitatory postsynaptic potentials; and long-term synaptic potentiation which has a critical function in learning and memory [12, 13]. Thus while the alcohol effect on the neuronal function is generally harmful, as far as the excitatory amino acids are concerned the inhibitory effect of alcohol may be beneficial in that it does afford some analgesic benefit. Indeed, aggressive treatment to the point of completely preventing the ethanol effect on the NMDA aside from complete abstinence, may also lead to a worsening of the neuropathic pain.

Dopamine and Sedation Ethanol induces dopamine release and potentiates 5-Hydroxytryptamine receptor activation. These receptors control dopamine release and this release is blocked by 5HT3 antagonists. Dopamine plays an important role in reward, reinforcement, and craving. Interestingly 5-HT3 receptor antagonism also reduces ethanol intake, and the ability to discriminate between water and alcohol in a murine model [14].

Adenosine Adenosine is a nucleotide and a critical component of RNA. It is an inhibitory neuromodulator in the nervous system. It modulates Ca++ channels and regulates neurotransmitter release. Ethanol impacts the adenosine axis which includes not only the nucleotide itself but also adenosine transporters and the A2 receptor. The relationship is summarized in Fig. 2.

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Acute Ethanol Exposure

Adaptive Desensitization to Adenyl Cyclase by Stimulating G Protein

Decreases Adenosine Uptake by Nucleoside Transporter

Extracellular Adenosine Accumulation

Increases cyclic AMP

Activates Adenosine A2 Receptors

Fig. 2  Summary of the effect of acute and chronic ethanol exposure upon the adenosine axis [15–20]

Acute ethanol exposure decreases adenosine uptake by the nucleoside transporter which leads to extracellular adenosine accumulation. The exposure also activates adenosine A2 receptors which leads to an increase in cyclic AMP. This results in an adaptive desensitization to adenyl cyclase production. At this point in the exposure ethanol is now required to maintain normal levels of cyclic AMP, which is physical dependence at the cellular level [21]. This desensitization appears to be due primarily to a decrease in mRNA for the guanosine triphosphate-binding component of Gs, Gαs [15–20]. The resultant decrease in Gαs causes the adenosine transporter to lose its sensitivity to ethanol inhibition. This is thought to be due to reduced cyclic AMP-dependent protein kinase activity. As a result, adenosine uptake is inhibited by acute ethanol exposure in naïve cells. Over time and with chronic alcoholic exposure this uptake becomes insensitive to ethanol inhibition which is now an example of cellular chronic tolerance to ethanol. Clinically this is significant because it suggests that the altered nucleoside transporter function that occurs in actively alcohol drinking individuals, may cause benefit from the resultant adenosine receptor antagonism. This antagonism could prevent many of the acute and chronic effects of ethanol on cyclic AMP signal transduction with subsequent prevention of acute intoxication and physical dependence.

Alcoholic Peripheral Neuropathy A component of autonomic dysfunction also exists in the constellation of alcoholic peripheral neuropathy [22–25]. Approximately 16–73% of chronic alcohol abusers suffer from this syndrome as determined by the cardiovascular reflex test. The wide range suggests difficulty in determining the exact number of individuals with this diagnosis. The cardiovascular reflex test includes the heart rate response to the Valsalva maneuver; the blood pressure response to standing; the blood pressure response to sustained hand grip; the sympathetic skin response; the methacholine

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test for iridic innervation; and the heart rate response to standing and deep breathing [26]. The presence of autonomic dysfunction may also be assessed by examining the sympathetic skin response which is defined as the momentary change of the electrical potential of the skin. It is elicited by any of a number of internal or externally applied arousal stimuli. The test is easy to apply but as a diagnostic tool it cannot be relied upon [27]. Where there is a high index of suspicion such as in the setting of alcoholic neuropathy or diabetic neuropathy, a positive test may be used to confirm clinical speculation that autonomic dysfunction exists. In a 2002 study Oishi, et al examined current perception threshold and sympathetic skin response in fourteen patients with diabetic polyneuropathy and 10 patients with alcoholic neuropathy. They found a negative correlation between the current perception threshold and the amplitude of sympathetic skin response. Both current perception threshold to 5  Hz and the SSR related to C-fibers, they surmised that both processes are impaired in these polyneuropathic syndromes [28]. In another study which attempted to correlate the SSR with sweating pattern in alcoholic neuropathy, the probable site of neural lesion, the type of peripheral nerve pathology, and to assess whether latency measurement could be used a reliable parameter. They studied males with alcoholic neuropathy and other peripheral neuropathy. They determined that SSR absence in alcoholic neuropathy results from a lesion in the efferent pathway and postulated that this absence was possibly due to demyelination as well as axonal pathology [29]. The nature of the toxic effects of both acute and chronic alcohol abuse are well described and have been discussed as a specific disease entity for almost a century. The term “alcoholic paralysis” itself was coined nearly two centuries ago, and was characterized by motility and mental function disorders [6, 22]. The pathogenesis of alcoholic neuropathy has been incorrectly attributed to thiamine deficiency (beriberi) which has been a secondary effect of overall poor nutrition habits in many who suffered from the disease. However, there are distinct differences between alcoholic neuropathy and thiamine deficiency disease and these will be described later in this chapter. As early as 1982, the amount of alcohol consumption that leads to the characteristic polyneuropathic changes was studied. The drinking habits of 156 consecutive polyneuropathic patients and 106 consecutive patients who suffered from pressure palsy were retrospectively examined. Thirty percent of polyneuropathic patients and 30% of pressure neuropathic patients became symptomatic when acutely intoxicated. There was also a gender (male) and age (older) predominance in the alcoholic neuropathic group; and other medical complications of heavy alcohol drinking (i.e., hepatic disease, seizures, and cerebellar signs) were seen in 54% of patients with polyneuropathy and in 6% of the patients with pressure palsies. It was also noted that heavy drinking also prolonged the disability due to pressure and worsened the prognosis of both neuropathies overall [30]. Another study that quantitated the amount of ethanol ingested and described the resultant neurologic derangement was conducted by Bosch et  al in 1979. While this work is clearly dated it does attempt to present specific evidence of a direct toxic effect of alcohol. In this study the group highlights the correlation of ethanol dose and neuropathic effect as

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measured by axonal transport of acetylcholinesterase [31]. While the study does appear to show this relationship, it is difficult to extrapolate the data to a clinical setting. This is because the group delivered an ethanol dose to the rats of 11–12 grams per kilogram body weight per day for 16 to 18 weeks. This is the equivalent of a 100-kilogram human imbibing 90 drinks per day of 45 percent alcohol. The clinical characteristics of alcoholic neuropathy with respect to demographic data were examined in 2017 by Ahmed, et al. The group outlined the typical age, sex, and socioeconomic status of the study subjects and correlated these with symptomatology and laboratory findings. While their work was severely limited by extremely small sample size (n  =  9) they did measure nutritional indicators, i.e., body mass index (BMI), vitamin B12 levels and serum albumin levels. These indicators were all found to be normal in this cohort. Their case series indicated that alcoholic neuropathy should be suspected in middle-aged, well-off patients presenting with painful neuropathy especially when no other etiology can be found. The group stated that habitual wine drinking with dinner or beer consumption over a period of years can trigger neuropathy. Perhaps more importantly they asserted that alcoholic neuropathy is likely secondary to direct toxic effects of alcohol rather than malnutrition [32]. Alcoholic neuropathy entails axonal degeneration with reduced density of both small and large fibers associated with neurite formation and subsequent axonal sprouting. Ethanol also causes cytoskeletal dysfunction which inhibits axonal flow; and activates protein kinase C epsilon (PKCε] signaling in primary afferent nociceptors and thus is critical to the sensitization of these nociceptors and the subsequent excitotoxicity that influences the formation of the neuropathic pain profile [33].

Molecular Mechanisms Involved in Alcoholic Neuropathy The proposed molecular mechanisms involved in the development of alcoholic neuropathy are discussed here and they suggest some of the novel therapeutic considerations (Table  1). The reader will no doubt notice that several of the mechanistic entities discussed date back more than two decades. However, the fact that our molecular, genetic, and technical understanding and abilities have expanded so much since those reports that several new adjuncts of the treatment of alcoholic and other neuropathies now have more readily realized potential. The early confusion between alcohol neuropathy and thiamine deficiency was due to overlap of confounding phenomena. The first was the frequent occurrence of diminished essential nutrient consumption in alcoholic patients and an associated

Table 1  Summary of proposed mechanisms of alcoholic neuropathy 1. Activation of Spinal Cord Microglia 2. Activation of mGlu5 Receptors in the Spinal Cord 3. Oxidative Stress Leading to Free Radical Damage to Nerves 4. Release of Pro-Inflammatory Cytokines Associated With Activation of Protein Kinase

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impairment of gastrointestinal absorption of these nutrients. This was believed to be secondary to a direct effect of alcohol and again the specific mechanism of this occurrence remains unknown. The second phenomenon was comprised of specific gastrointestinal and hepatic events. These included the diminution of thiamine by alcohol in the intestine; the reduction in hepatic stores of thiamine and inhibition of the activating phosphorylation step of thiamine to form thiamine diphosphate [34]. One of the earliest discussions of the mechanism of alcoholic neuropathy suggested that lipid microemboli might cause nerve infarction from vascular thrombosis. In patients with this syndrome it was suggested that the fat emboli were derived from a fatty liver, the result of alteration in the physical state of the serum lipids or the initiators of local fibrin or platelet deposition via the lipid effect on the thrombotic cascade. These authors proposed the performance of nerve biopsies in patients with acute alcohol peripheral to search for intravascular occlusion by lipids; and to use this finding to guide subsequent control of serum lipid levels and thus prevent extension of the neuropathy [35]. While this approach may seem archaic by current therapeutic understanding it did suggest some potential molecular pathways. Exploration of the “direct effect” origin of alcoholic neuropathy is based upon clinical observation and anecdotal evidence. This is to be expected as conducting true, randomized blinded control trials to examine the neurotoxicity of alcohol in a human model raises severe and justified ethical questions. Yet the anecdotal reports trigger the direction of subsequent, pertinent bench research. For instance, Singh, et al, described the case of a middle-aged male who swelling and weakness of muscles in the lower limbs following an episode of binge alcohol drinking. The patient had acute myoglobinemia and also developed acute renal failure which required dialysis. The mechanism of myopathy in this setting is not known but the report speaks to the need for appropriate studies to unpack the cellular interaction [36]. A human study in 2005 examined the occurrence of large and small fiber neuropathy among alcohol-dependent subjects. In an indirect attempt to define a relationship of neuropathy with the pattern of alcohol abuse, they sampled 98 consecutive alcohol-dependent subjects. Polyneuropathy was graded using the neuropathy symptoms score and the neurologic disability score. In addition, the group examined nerve conduction velocities, and quantitative sensory tests. Neuropathy significantly correlated with subject age, duration of alcohol abuse, liver dysfunction, macrocytosis and blood sugar levels upon admission. The group arrived at a somewhat derivative indication that a direct toxic effect of alcohol on peripheral nerve fibers was the main etiologic factor of alcoholic polyneuropathy. Interestingly they also implicated hyperglycemia and impaired vitamin B12 utilization as potential causative factors in the development of alcoholic neuropathy [37]. A general molecular mechanism of the development of alcoholic neuropathy was summarized in a review by Chopra and Tiwari in 2012. They iterated some of the working explanations for the syndrome. Several mechanisms have been proposed as relevant contributors to alcoholic neuropathy. These included activation of spinal cord microglia oxidative stress leading to free radical damage to nerves;; inflammatory cytokine-mediated activation of protein kinase C; [38] activation of mGlu5 receptors in the spinal cord and activation of the sympathoadrenal and the

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hypothalamo-­pituitary-adrenal axis; and a direct toxic effect of alcohol; [4] involvement of extracellular spinal-regulated kinases [ERKs] or classical MAP kinases. There is also speculation that excessive alcohol intake may lead to involvement in the endogenous opioid system; [39–41] as well as in the hypothalamo-pituitary-­ adrenal system [42–44]. The demyelination recognized in alcoholic neuropathy is thought to be the result of diminished axonal flow. Ethanol and its toxic metabolites impact metabolic pathways of the nucleus, peroxisomes, the endoplasmic reticulum and lysosomes [4]. The critical, harmful metabolite of ethanol is acetaldehyde. IMAGE-Acetaldehyde] A certain percentage of acetaldehyde escapes metabolism by the usual pathways and binds irreversibly to normal proteins to create cytotoxic proteins that disrupt the normal function of neurons [4]. The exact amount of alcohol needed on a weight-­ by-­weight basis is not known, but again it has been shown that the severity of alcoholic neuropathy varies directly with both the duration and amount of alcohol consumption. There is temporal prominence of the occurrence of alcohol-related peripheral nervous system dysfunction over alcohol-related deleterious effects on the central nervous system because of the blood brain barrier. This system defers the metabolic and toxic influences on brain function for a significant period of time.

Direct Toxic Effects of Ethanol or its Metabolites As mentioned earlier, acetaldehyde is considered the most chemically disruptive metabolite of alcohol metabolism. Acetaldehyde is hepatotoxic via the generation of acetaldehyde-protein adduct formation, depletion of glutathione, microtubular impairment, inhibition of DNA repair; impairment of mitochondrial electron transport chain and stimulation of immunologic reactivity. In cortical neuronal cultures acetaldehyde derived advanced glycation end-products (AA-AGE) produced a dose-dependent increase in neuronal cell-death; but the neurotoxicity of AA-AGE is attenuated by anti-AA-AGE specific antibody [45].

Oxidative Stress and Alcoholic Neuropathy One of the most convincing arguments for the mechanism of alcoholic neuropathy may be found in the generation of oxidative products and the reduction of the free radical scavengers that bot result from elevated amounts of ethanol intake. In 2007, Lee et  al, showed that at the fundamental level, reactive oxygen species, (ROS) played critical roles in the development and maintenance of capsaicin-induced pain via central sensitization in a dorsal horn neuronal murine model [46]. One proof of this mechanism was set forward by Padi, et al, who used the administration of minocycline to prophylactically inhibit pro-inflammatory cytokine release and oxidative and nitrosative stress in mononeuropathic rats. This administration prevented the development of neuropathy but, interestingly, had no effect on acute pain [47]. The work highlighted the role ROS and RNS in neuropathy and was fundamental in the

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attempt to link alcohol ingestion to oxidative-nitrosative stress and neuropathic pain. Work upon the controllers of oxidative stress reinforced this concept. The downregulation of antioxidant enzymes such as superoxide dismutase and catalase, and an increase in lipid peroxidation were noted in sciatic nerves of diabetic rats with established neuropathic pain [48]. With these and other studies as a foundation, we look to studies that show the relationship of ethanol in the ROS, RNS and other free radical dysregulation processes. The cytochrome P450-dependent conversion of ethanol to acetaldehyde results in that moiety functioning to increase reactive oxygen species, with concomitant changes in the oxidation/reduction balance [49]. Lipid peroxidation products such as malondialdehyde have been shown to increase significantly in the sciatic nerves of rats fed an ethanol-containing diet [50]. Chopra, et al, subsequently found a significant increase in lipid peroxide concentrations and a marked decrease in the activity of the free radical scavengers, reduced glutathione, superoxide dismutase, and catalase in the sciatic nerve of rats with hyperalgesia and allodynia given an ethanol-enriched diet [4].

Neuroinflammation Ethanol is recognized to caused neuroinflammation. In the developing CNS ethanol induces increased expression of proinflammatory cytokines and chemokines including IL-1β, TNFα, and chemokine 9C-C motif ligand 2, (CCL2). In the adult CNS transcription factor NF-κB expression is increased and this factor plays an important role in activating multiple genes encoding proinflammatory molecules such as cytokines and chemokines. Ethanol also triggers TLR 4 signaling in glial cells in a manner that mimics the pathogen-induced response [51]. Ethanol thus also activates the expression of downstream transcription factors such as AP-1 and NF-κB with subsequent elaboration of proinflammatory cytokines, chemokines, COX-2 and iNOS [52]. While these responses have indeed been noted in the CNS, isolated studies in the peripheral nervous system reveal expression of similar generators and products of neuroinflammation. The specific mechanisms in this peripheral environment have not been as well-described, but interpolation from the beneficial effects of anti-­ oxidant therapies, at least in the limited animal models, it appears that the neuroinflammatory process plays an important role in the development of peripheral neuropathic pain.

Protein Kinase The role of protein kinases in alcoholic neuropathy is an exciting consideration given what we know of the interaction of these kinases with their receptors and the resultant receptor conformational changes. Protein kinase C (PKC) is involved in receptor sensitization and desensitization; the modulation of membrane structural events that are critical to the adaptation to repetitive neuronal activity secondary to

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noxious stimuli; the meditation of the immune response; the regulation of transcription; the regulation of cellular growth; and learning and memory [4]. It is the most well-described with regards to neuropathic pain. It is discussed elsewhere in this textbook (Chap. 2), but with respect to work conducted related to alcoholic neuropathy we turn to Dina, et al. In 2000, this group utilized a murine model in which an alcohol-enriched diet was administered. They found mechanical hyperalgesia, thermal hyperalgesia, and mechanical allodynia in addition to decreased mechanical threshold of C-fibers. They confirmed the role of the protein kinase in this process when they administered non-selective PKC or selective PKCε inhibitors intradermally and observed attenuation of the hyperalgesia [53]. Protein kinase A and protein kinase C cascades appear to be impacted by ethanol. However, this has not been shown directly in a mechanistic sense. Rather, the attenuation of the hyperalgesia of alcoholic neuropathy in a murine model following administration of PKC inhibitors implies a significant role of these kinases in this syndrome [38]. Miyoshi, et al, found that chronic ethanol consumption significantly decreased the mechanical nociceptive threshold in a murine model. In this work the injection of the selective PKC inhibitor (5)-2,6-diamino-N-[[1-(oxotridecyl)-2 piperidinyl] methyl] hexanamide dihydrochloride (NPC15437), attenuated the hyperalgesia. The group also found that phosphorylated PKC was significantly increased in the spinal cord following chronic ethanol ingestion [54]. Inhibitors of the extracellular signal-regulated kinases (ERKs) and mitogen activated protein kinases (MAPKs) results in the attenuation of ethanol induced hyperalgesia. The role of these kinases is implicated in the development of ethanol induced neuropathy and the avenue for specific mechanistic interventions is made a bit wider [4, 55].

Glial Cells It is well known that spinal cord glial cells, astrocytes, and microglia are activated by neuropathic pain or peripheral inflammation. In addition, both astrocytes and microglia are activated by several member molecules of the nociceptive cascade. These include substance P, calcitonin-gene related peptide (CGRP), ATP and excitatory amino acids from primary afferent terminals. Astrocytes and microglia are also activated by viruses and bacteria [56, 57]. Ethanol has been shown to activate spinal microglia in a murine model after 5 weeks of ethanol-enriched dietary supplementation. This activation was observed with a concurrent decrease in mechanical threshold [39]. What has not been shown, beyond speculation at least, is whether the excitatory amino acid transporter (EAAT) system is affected by ethanol administration. The cysteine-aspartic acid proteases or caspases play an important role in apoptosis, necrosis and inflammation. Activation of proteolytic enzyme system caspases  is triggered by translocation of the nuclear factor- kappaB (NFκB) to the

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nucleus [58]. Jung, et al, demonstrated in a murine model that chronic ingestion of ethanol resulted in increased amounts of oxidative damage, translocation of NFκB, and activation of PKC and NFκB which results in DNA fragmentation and ultimately increased neuronal death [59]. Then Izumi, et al, in that same year demonstrated that a 24 hour exposure of ethanol ingestion on the seventh postnatal day resulted in significant apoptotic neuronal damage throughout the forebrain. The authors speculate that chronic ethanol consumption may be responsible for initiating neuropathic cellular changes through activation of the caspase cascade [60]. Another mechanism of neuropathic pain affected by chronic ethanol ingestion involves the metabotropic glutamate receptors (mGluR). These receptors are abundant in spinal cord dorsal horn as well as on primary afferent nerves. The mechanical nociceptive threshold is decreased within 5 weeks following ethanol exposure in a murine model [61]. immunostaining of the membrane fraction of spinal cord sections showed significant increases in the number of membrane-bound mGluR5 following ethanol exposure. The increased number of membrane-bound mGluR5 receptors that results after consumption of an ethanol-enriched diet is thought to lead to a persistent activation of protein kinase C in the dorsal horn with subsequent induction of neuropathic pain behavior [4, 61]. Alcoholic consumption also increases the p-Ser1303-NR2B subunit of the NMDA receptor in the spinal cord of rats receiving an ethanol-enriched diet [39]. Ethanol may play a role in the destabilization of the μ-opioid receptor and it may  be mediated by PKC [39, 62]. PKC mediates the phosphorylation of opioid receptor complexes in the neuronal membrane results in an imbalance of μ-removal and replacement in the neuronal membrane with a net reduction in μ-receptor concentration and a reduced sensitivity to morphine-induced antinociception. There is also an increased release of glucocorticoids and catecholamines following alcohol consumption [42–44]. In fact adrenal medullectomy has been shown to prevent and also to reverse the pro-nociceptive effects of ethanol consumption [63]. It should be remembered at this juncture that both catecholamines and glucocorticoids have receptors on sensory neurons. The role of glial cells will also be noted again in the therapeutic section of this chapter as the manipulation of these cells may prove to be valuable interventions in the treatment of neuropathies of alcoholic as well as other etiologies.

Cytoskeletal Effects Alcohol impairs axonal transport and cytoskeletal properties. In a 2006 work, Koike, et al, included in their review the effect of ethanol upon neuronal structural and nutrient delivery systems. They summarized that ethanol exposure causes a reduction in neurofilament-associated phosphatase activity which results in an increase in phosphate content of neurofilament proteins. Phosphorylation of microtubule-­associated proteins is altered by ethanol exposure and impairs axonal transport [63–66].

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Clinical Presentation The presentation of alcoholic neuropathy is not consistent (Tables 2 and 3). There are a number of cases in the literature in which the disease mimics Charcot arthropathy which can often otherwise be associated with diabetes mellitus; [67] and/or Guillain-Barre, in which alcoholic neuropathy departs from its usual slowly progressive polyneuropathic pattern, to encompass an extraordinarily rapid progression pattern which evolves in a matter of a few days [67–70]. Other presentations of alcoholic neuropathy have been described. For instance, involvement of the eighth cranial nerve was described in a 55-year-old male chronic alcoholic who presented with symptoms of hearing loss, balance disturbance, and facial weakness. There were also symptoms of peripheral polyneuropathy but the primary symptomatology was centered about the vestibulocochlear nerve. The patient was treated with a translabyrinthine eighth cranial nerve transection in order to achieve symptomatic improvement. Histopathologic examination of the specimen revealed extensive degeneration of both myelinated and unmyelinated fibers in both cochlear and vestibular divisions. Which were compatible with experimentally induced Wallerian-like degeneration [71]. Similarities of alcoholic neuropathy to Vitamin B1 or thiamine deficiency (beriberi) have also been described in some of the earlier literature and this is responsible for some of the conflation of the two syndromes which was the result of concomitant nutritional derangement. In one case from 1982 a 47-year-old female alcoholic presented with a sensorimotor disturbance with glove and stocking type distribution. Histologic analysis of teased fibers from a sural nerve biopsy was performed. The analysis revealed that 36% of fibers showed signs of axonal degeneration while 12% of the fibers demonstrated segmental demyelination. Fiber density examination showed a decrease in the density of large myelinated fibers while small myelinated and unmyelinated fibers displayed

Table 2  Summary of typical Alcoholic Neuropathy-related symptoms Symptom Painful Sensations Weakness Progression of Sensory and Motor Dysfunction

Characterization With or Without Burning Distal extremities Proximal Extension to Arms and Legs

Table 3  Summary of typical Alcoholic Neuropathy-related pathologic findings Reduced Nerve Fiber Density  Small Myelinated Fibers > Large Myelinated Fibers  Unmyelinated Fibers > Large Myelinated Fibers Widening of Consecutive Nodes of Ranvier  Segmental Demyelination and Remyelination

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normal density. These clinical and histopathology findings are all consistent with those found in beriberi, yet this patient suffered no such deficiency by dietary analyses [72]. A later study by Koike et al in 2001 emphasized the findings of distinct differences between alcoholic neuropathy and vitamin deficiency. In this work, 18 patients with painful alcoholic polyneuropathy and normal thiamine status were assessed for clinicopathologic features. The group found that in alcoholic polyneuropathy, densities of small myelinated fibers and unmyelinated fibers were more severely reduced than the density of large myelinated fibers, except in patients with a long history of neuropathic symptoms and marked axonal sprouting [73]. This is in direct contradistinction to the pathologic findings in the 1982 work reported by Shiraishi [72]. Koike iterates this finding of small-fiber predominant axonal loss in alcoholic neuropathy and large-fiber-predominant axonal loss in thiamine-deficiency neuropathy in a follow-up study in 2003. The group distinguishes the two processes on a clinical basis asserting that alcoholic neuropathy symptoms are sensory dominant and slowly progressive with predominant impairment of superficial sensation especially nociception. Thiamine deficiency neuropathy on the other hand is manifested as a motor-dominant and acutely progressive pattern, with impairment of both superficial and deep sensation. They attributed this difference to a direct toxic effect of ethanol or its metabolites, [74] and further distinguished alcoholic neuropathy from other neuropathies in a 2008 study [25]. A coinciding physiologic derangement of alcoholic neuropathy involves the gastrointestinal tract. As early as 1968 researchers learned that a selective deterioration of esophageal peristalsis developed in a number of patients with chronic alcoholism. The study employed intraluminal manometry. Ten patients with alcoholic neuropathy were compared with 6 chronic alcoholic patients who exhibited no signs of peripheral polyneuropathy. None of the patients were reported to have dysphagia or any other esophageal symptoms. The selective deterioration of esophageal peristalsis was associated with the presence of symptomatic peripheral neuropathy [75]. A later study expanded upon this relationship. Chronic alcoholics have increased dyspepsia, delayed gastric emptying and oro-cecal transit time but faster gallbladder emptying with slightly accelerated colonic transit. They  also exhibit  sympathetic dysfunction manifested by an impaired local sweat production stimulated by iontophoretically administered cholinergic agonists and by thermoregulatory sweat testing [76]. The GI dysfunction of alcoholics is consistently associated with neuropathy. Abstinence of one-year duration is unlikely to reverse the derangement. Whether this is a continuation of the dysphagia, hoarseness and weakness process described by Novak in 1974 is unknown [77].

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Diagnosis The definitive, non-invasive diagnosis of alcoholic neuropathy without laboratory examination is extremely difficult since so many neuropathic syndromes overlap symptomatically. Hence, strict attention must be made to the patient’s substance history, the time course of symptom history, and the pattern and quality of findings on physical examination. These are summarized in Table 2, above. Aside from this, there are non-invasive laboratory studies that can be employed that are useful in distinguishing this syndrome. Hoffmann’s reflex, or the H-reflex refers to the reaction of muscles after electrical stimulation of sensory fibers. It is analogous to the spinal stretch reflex. The H-reflex differs from the spinal stretch reflex in that it bypasses the muscle spindle. This is valuable in assessing modulation of monosynaptic reflex activity in the spinal cord. It can be used to evaluate the nervous system response in various conditions [78]. The H-reflex is reported to be the most sensitive test to measure nerve conduction velocity in alcoholic neuropathy [79]. Regarding the use of conventional nerve conduction studies, Alexandrov, et al, compare residual latency, (or the calculated time difference between the measured distal latency of a sensory nerve and the expected latency); with the distal motor latency (or the quotient of the terminal latency-obtained by dividing the distance between the stimulation and the registration point by the latency of response). The group found that distal motor latencies and residual latencies were prolonged in the early stages of diabetic neuropathy and alcoholic neuropathy, while the latencies were normal in non-neuropathic patients (Fig. 3). Distal Motor Latency

Normal Motor Neuron

Normal 10 mV

5 ms

Demyelinating Disease

Demyelinating

Distal motor latency prolonged

Nerve conduction velocity slow Axonal Axonal Degeneration

Reduced action potential

Fig. 3  Graphs of motor latency in diabetic neuropathy and alcoholic neuropathy; and in the normal setting. Note the latency is normal in non-neuropathic patients

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Distal Motor Latency Normal Motor Neuron

5 ms

10 mV

Demyelinating Disease Distal motor latency prologned

Nerve conduction velocity slow Axonal Degeneration

Reduced action potential

Fig. 3 (continued)

Treatment The treatment of alcoholic neuropathy is unique in that it is the one neuropathic process in which the exact causative agent is known and can, in theory, be added to or subtracted from the experimental environment. This allows an examination of effects in either a temporal or duration of exposure sense; a specific dosing sense, i.e., intermittent dosing as well as cumulative dosing; or both. In addition, alcoholic neuropathy is also a syndrome in which several specific mechanistic sites of impact have been described. Thus, we can postulate where and how any of a number of specific interventions may be introduced in order to potentially effect a change in the progression of the disease or to halt it altogether. Yet these same characteristics create significant ethical dilemmas which must arise whenever any truly randomized control trials involving ethanol dosing and specific treatments are considered. For this reason, we are left with examinations in non-human models and extrapolations from these. One promising consideration that does exist is the performance of molecular mechanistic studies ex vivo from human candidates and subsequent

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extrapolation from these. This section explores a number of current interventions. Several of them are described only anecdotally and thus have not been applied on a wide scale.

Liver Transplantation It seems intuitive that liver transplantation used in conjunction with abstinence would improve at least one limb of the array of derangements that lead to alcoholic neuropathy. However, this does little to account for the direct and long-lasting effects of EtOH on other organ systems. A study by Gane in 2004 stated that 10–20% of all liver transplants are performed for end-stage alcoholic liver disease. Yet the list of severe, extrahepatic end-­ organ derangements from alcoholism that preclude an individual from receiving a liver transplant includes neuropathy. The group reported one patient who was able to receive a hepatic allograft despite having decompensated alcoholic liver disease and moderately severe peripheral neuropathy. At 12 months following successful transplantation the patient displayed reversal of muscle weakness and associated recovery in sensory and motor nerve conduction velocities. They concluded that peripheral neuropathy in a patient with alcoholic cirrhosis may resolve following liver transplantation and should not be a contraindication to transplantation [80].

Sodium Channel Blockade Blockade of sodium channels and subsequent interruption of neuronal conduction as a means of controlling existing nociceptive input into the central nervous system, as well as rendering a limb or body region insensate to potential noxious stimuli as a form a surgical exclusion  is well described. Typically, local anesthetics have been used to accomplish this task and it is a logical sequel that they have been employed in the attempt to control alcoholic neuropathic pain. There have been few studies in the literature that have utilized intravenous lidocaine in this role. In 1999, Babacan, et al, presented a single alcoholic patient with a polyneuropathy due to folic acid deficiency who was successfully treated with a lidocaine infusion following unsuccessful treatment of symptoms by folic acid replacement [81]. Another sodium channel blocker, mexilitene, had been used to good effect beginning almost a decade earlier in small studies by Beroniade, et al; [82] and then by Nishiyama, et al. [83]. In the Nishiyama report, five patients suffering from painful alcoholic peripheral neuropathy were given oral mexilitene at a minimum dose of 300 milligrams per day and received effective pain relief, especially of the neuropathic component which they described as the “tingling” sensation [83]. It must be noted that the role of local anesthetics, especially lidocaine, in the treatment of alcoholic and other neuropathies appears not to be limited to the blockade of sodium channels. Landmark work by Werdehausen et al in 2012 implicated a metabolite of lidocaine, monoethylglycine xylidide, in the cessation of

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neuropathic pain via central glycinergic mechanisms [84].Specifically, there exists an astrocyte-associated glycine transporter system (GlyT1) which mediates in part the availability of the inhibitory neurotransmitter, glycine in the synaptic cleft of tripartite synapse. The effects of lidocaine in the treatment of neuropathic pain cannot be explained by its action upon voltage-gated sodium channels. These effects include anti-inflammatory [85] and prolonged antinociceptive properties [86–88]. The authors performed a direct comparison of the chemical structures of known GlyT1 inhibitors such as sarcosine and noted important similarities especially with lidocaine metabolites, N-ethylglycine (EG) and MEGX. They were able to show that the presence of these metabolites were able to diminish glycine uptake in primary astrocytes. This continues the question of whether there is a similar mechanism of antinociception at work when lidocaine is administered for the relief of neuropathic pain long after cessation of its administration [85, 86, 89].

Spinal Cord Stimulation Spinal cord stimulation (SCS) has been typically used only when all other less invasive therapeutic options have been exhausted. While an in-depth discussion of neuromodulation is beyond the scope of this chapter, a brief review of its principles are very pertinent in relation to the treatment of neuropathic pain and especially alcoholic neuropathy. SCS has been described infrequently in the treatment of this syndrome and even then only anecdotally. The stimulator electrodes are placed via a sterile percutaneous technique onto the dorsal column of the spinal cord. Activation of the electrodes in this position stimulate the large diameter, non-nociceptive, myelinated fibers of the peripheral nerves (A-β fibers) which inhibits the activity of small nociceptive projection Aδ and C fibers in the dorsal horn of the spinal cord [90, 91]. In addition SCS activates gamma amino butyric acid type B (GABA-B) and adenosine A-1 receptors that also lead to pain modulation. [90–93]The currently accepted indications for the use of SCS are failed back surgery syndrome with radicular pain; complex regional pain syndrome; peripheral neuropathy; phantom limb pain; angina; and ischemic limb pain [94, 95]. In 2010, however, Yakovlev, et al, reported effective analgesia using SCS in a 46-year-old female who had failed standard therapy for her alcoholic neuropathy. While there is no question that this data is purely anecdotal, it does raise the question of whether the list of indications for the use of SCS could be expanded to include alcoholic neuropathy. Clearly, more clinical studies would be needed in order to validate this inclusion [96].

Therapy The current therapies for treating alcoholic neuropathy are directed towards stopping the ongoing injury to peripheral nerves as well as restoring normal neuronal function. If these goals cannot be achieved simply via abstinence and repair of any nutritional derangements, then the next and frequently final therapeutic step is the

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use of the “usual suspects” in the treatment of neuropathic pain in general. These drugs are used in treating the acute dysesthetic pain of alcoholic neuropathy. The conventional drugs used in this setting are the gabapentinoids (gabapentin and pregabalin); amitriptyline or other tricyclic antidepressants and over-the-counter remedies such as acetaminophen and aspirin. Other drugs are currently in use and their pattern of deployment is often based upon regional differences and availability.

Benfotiamine Benfotiamine is a lipophilic thiamine prodrug which has been shown to prevent retinal and renal changes in animal studies caused by oxidative stress (Fig. 4) [97]. It is a synthetic 5-acyl derivative of thiamine. In the absence of a nutritional vitamin deficiency component, chronic alcohol consumption has been shown to lead directly to a decrease in the active coenzyme form of thiamine (thiamine diphosphate- TDP) in a murine model. Dietary supplementation with benfotiamine significantly increased concentrations of TDP and total thiamine compared to thiamine hydrochloride [98]. In 1998, Woelk, et al, conducted a randomized control trial that specifically compared the effect of benfotiamine alone with a benfotiamine-B vitamin complex or placebo in 84 alcoholic patients. The group found that benfotiamine was statistically superior to both the benfotiamine complex and the placebo with respect to motor function, paralysis and overall neuropathy score [99].

Alpha Lipoic Acid The free radical scavenger, alpha lipoic acid is a naturally occurring micronutrient synthesized by humans (Fig. 5). It assists in repairing oxidative damage and regenerates endogenous antioxidants such as glutathione as well as vitamin C and Fig. 4 Benfotiamine

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Fig. 5  Alpha Lipoic Acid

vitamin E. it also chelates metals and promotes glutathione synthesis. Alpha lipoic acid is absorbed from the small intestine and distributed to the liver via the portal system and the systemic circulation. It is found in certain body tissues intracellularly, intramitochondrially, and extracellularly [100]. The agent has been used to treat neuropathic pain in Europe for decades [4]. In murine models of streptozotocin-induced diabetes, alpha-lipoic acid was found to increase glucose uptake by nerve cells [101]. In addition the drug also increases nerve myo-inositol concentrations, [101, 102] normalizes the intracellular NAD:NADH ratio and increases neuronal blood flow [102].

Acetyl-L-Carnitine Acetyl-L-carnitine has not been specifically employed in the treatment of alcoholic neuropathy. A recent systematic review of the literature did determine that the agent possessed global efficacy in producing significant pain reduction, improving nerve conduction parameters with a clinically acceptable margin of safety [103].

Miscellaneous Agents Other agents that have shown some efficacy in laboratory models or in other neuropathies but remain as yet unscreened in alcoholic neuropathy per se include α-tocopherol and tocotrienols [104]. More specific to a possible pathogenetically targeted treatment of alcoholic neuropathy in our view is methylcobalamin which addresses hypomethylation in the central nervous system. Hypomethylation is the result of a fall in the ratio of s-adnosylmethionine (SAM) to s-­adenosylhomocysteine [105]. The resultant deficiency in SAM hinders critical methylation reactions in the myelin sheath. A systematic review of the literature by Sun, et al, was limited to diabetic neuropathy but still showed beneficial effects. A logical sequel to this work would be similar, rigorous trials in the setting of alcoholic neuropathy.

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Novel Therapeutics Myo-Inositol Many of the interventions have commonality with the treatments of other neuropathies. This suggests that these interventions may not need to be as specific on an etiologic basis as may have been previously thought. However, the fact that more specific interventions on a mechanistic basis need to be sought has not change. For instance, myo-inositol, an essential component of the phospholipids that make up nerve cell membranes has been shown to be deficient in diabetic neuropathy (Fig. 6). Interestingly, high myo-inositol concentrations were associated with nerve regeneration in a human study comparing type 1 diabetics with neuropathy with subjects who had type 1 diabetes without neuropathy, and subjects who had normal glucose tolerance. This regeneration was shown by demonstrating increased nerve fiber density in sural nerve biopsies [106]. The beneficial effect of supplemental myo-­inositol upon motor nerve conduction has also been demonstrated. In a streptozotocin-­diabetic murine model, myo-inositol partially prevented the decrease in motor conduction velocity. Moreover, an analogue of myo-inositol, D-myo-inositol-1,2,6-trisphosphate completely prevented a reduction in nerve conduction velocity [107].

N-Acetylcysteine Again a mechanistic similarity suggests possible efficacy in the treatment of alcoholic neuropathy (Fig. 7). The amino acid N-acetylcysteine is a potent antioxidant which assists in the enhancement of glutathione levels. In a murine model of streptozotocin-­ induced diabetes and subsequent neuropathy, N-acetylcysteine Fig. 6 Inositol

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Fig. 7 N-Acetyl-Cysteine

administration corrected both decrements in nerve conduction velocity and endoneurial blood flow [108]. Later, Park et al, using a murine model of chemotherapy-­ induced peripheral neuropathy found that neuronal apoptosis caused by cisplatin could be completely blocked if the cells were pre-incubated with N-acetylcysteine [109]. It is the similarity of the role of oxidative stress in the neuropathy in both these experimental settings that suggests potential efficacy in the treatment of alcoholic neuropathy.

Coenzyme Q 10 Coenzyme Q 10 (CoQ10) is a naturally occurring substance found in high levels in the body in the heart, liver, kidneys and pancreas. Several studies have been performed attempting to determine whether this coenzyme plays a role in the relief of the symptoms of alcoholic neuropathy. In 2013, Kandhare, et  al used a murine model to study the combination of vitamin E and (CoQ10) for the treatment of alcoholic-induced chronic neuropathic pain. They showed that there was a significant decrease in levels of endogenous calcium, oxidative-nitrosative stress markers, TNF-α, IL-1β, and IL-4 level. In addition, they showed that CoQ10 alone could also present behavioral, biochemical and effects of ethanol administration. This was accomplished by its inhibition of oxidative and nitrosative stress; inhibition of the release of pro-inflammatory cytokines and the protection of polymerase-γ (pol-γ). Coenzyme Q 10 protection of pol-γ is of particular importance because of the role the polymerase plays in the maintenance of mitochondrial DNA (mtDNA) which in turn is critical to mitochondrial oxidative phosphorylation processes which prevent organ dysfunction, [110] and specifically axonal sensorimotor neuropathy [111, 112]. The neuroprotective effect was further improved when CoQ 10 was administered in combination with α-tocopherol [113].

Curcumin Curcumin is the polyphenol found in the spice, turmeric (Fig. 8). It has been shown to be of value in the management of oxidative and inflammatory conditions, metabolic

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Fig. 8 Curcumin

syndrome, arthritis, anxiety and hyperlipidemia. The majority of these health benefits have been attributed to its anti-oxidant and anti- inflammatory effects [114]. It is logical, then, that the molecule’s effect upon alcohol neuropathy would be explored. In 2012, Kandhare, et al, examined the combination administration of curcumin and α-tocopherol for 10 weeks in a murine model of alcohol-induced neuropathy. It was noted this administration significantly improved nerve function, molecular and biochemical parameters; and DNA damage in a sciatic nerve preparation all in a dose dependent fashion. They also asserted that the main mechanism of action of curcumin in the management of alcoholic neuropathy was via inhibition of pro-­ inflammatory mediators such as tumor necrosis factor-α and interleukin 1 β. Curcumin and the selective phosphodiesterase 5 inhibitor, sildenafil were examined with respect to their combined and separate efficacies in the treatment of alcoholic neuropathy. Individually the agents were shown to significantly attenuate the symptoms of alcohol induced neuropathy. At both low and high doses. Concomitant administration of curcumin and sildenafil was found to significantly improve nerve function, biochemical and histopathological parameters all at lower dose than when the drugs were administered alone. Based upon these findings and the relative safety and common use of these agents it may be logical to consider human studies utilizing curcumin/sildenafil therapy for treatment of alcohol induced neuropathic pain [115].

Rolipram Another phosphodiesterase inhibitor rolipram (Fig. 9) was studied. Rolipram inhibits the phosphodiesterase 4 (PDE4) and differs from sildenafil (a PDE5 inhibitor) in that it hydrolyzes the phosphodiester bond of cyclic adenosine monophosphate, while sildenafil hydrolyzes this same bond in cyclic guanosine monophosphate. Han, et al, undertook electrophysiologic and behavioral examination of the effect or rolipram upon alcohol-induced neuropathy in a murine model. They found that in rolipram treated animals via intraperitoneal injections, there was a  decrease in mechanical allodynia. The group concluded that rolipram might have clinical implications in humans and suggested that it should be tested in this setting [116].

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Fig. 9 Rolipram

Fig. 10 Quercetin

Quercetin Quercetin is a proven antioxidant that has been shown to have some efficacy in other neuropathies (Fig. 10) [117]. Thus it was a logical consideration that it would be tested in the setting of alcohol induced neuropathy. In the most definitive study performed study performed in this setting, Raygude, et al, employed an alcoholic neuropathy-induced murine model. They found that chronic treatment with quercetin attenuated allodynia, hyperalgesia and impaired nerve conduction velocity. They also found that there was a decreased level of membrane bound sodium-potassium dependent-ATPase which can function as an amplifier for reactive oxygen species (ROS) generator which in turn leads to oxidative stress [118]. Quercetin also decreased levels of malondialdehyde, [119] a marker of myeloperoxidase, [120] and nitric oxide  which are markers of oxidative and/or nitrosative stress. They concluded that quercetin was important in the interruption of the oxidative and nitrosative stress generated that is responsible in part for alcoholic neuropathy and may be deemed neuroprotective [121].

Resveratrol Resveratrol is a polyphenol that belongs to the stilbenoids group (Fig. 11) and it has been shown to possess a high antioxidant potential. It is also a phytoalexin, i.e., a

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Fig. 11 Resveratrol

Fig. 12 Tocotrienol

plant synthesized substance that demonstrates antimicrobial and anti-fungal effects [122]. Based upon work in a murine model, resveratrol inhibits inflammatory signaling by inhibiting the production of oxidative and nitrosative stress mediators (TNF-α, IL-1β, and TGF-β1), and thus can be considered neuroprotective. As with other promising agents for the treatment of alcoholic neuropathy resveratrol has not been tested in humans.

Tocotrienol The name tocotrienol refers to an unsaturated isoform of Vitamin E. It is unique from the saturated isoforms or the tocopherols in that it suppresses the inflammatory transcription factor NF-κB (Fig.  12). Tocotrienols also quench free radicals by inducing antioxidant enzymes such as superoxide dismutase, [123] quinine oxidoreductase, [124] and glutathione peroxidase. Among the other effects of tocotrienols that may be deemed beneficial, is the antiproliferative effect of the drug via the inhibition of mitogen-activated protein kinases [125, 126]. Tiwari, et al, demonstrated the relief of oxidative stress in an alcohol-induced neuropathy murine model in 2009 and again in 2012 when he reported that they were able to demonstrate the above-mentioned increases in glutathione and super dismutase [125–128].

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Fig. 13  Epigallocatechn-3-­gallate

Epigallocatechin-3-Gallate (EGCG) Epigallocatechin-3-gallate (EGCG) is a flavan-3-3′, 4′, 5, 5′,7-hexol and a catechin (Fig. 13). It has a role as an antioxidant, a plant metabolite, and a food component. It is found in almonds, broad beans and in green and black tea [129]. EGCG also displays the ability to limit the production of oxidative and nitrosative stress in a murine model and to also diminish the downstream effects of allodynia and hyperalgesia [130]. As with other proposed pharmacologic interventions for the treatment of alcoholic neuropathy, clinical studies in humans must be conducted.

Gene Manipulation Genetic variation among those who drink alcohol was studied in an attempt to identify those most susceptible to alcohol misuse syndrome and its sequelae. There is a frequent occurrence of hyperhomocysteinemia in alcohol-dependent subjects. This is noted especially in those who also suffer severe withdrawal symptoms. The methylenetetrahydrofolate reductase gene (MTHR) codes for an essential step in the remethylation process of homocysteine to methionine. A reported common polymorphism is the substitution of thymine for cytosine at the 677 position on the usual C-C allele. This substitution (C677T) is associated with increased thermolability of the 5, 10 methylene tetrahydrofolate reductase enzyme and thus reduced activity [131]. In a 2008 study, Saffroy et al, noticed that alcohol-dependent subjects who had the T-T allele at position 677 displayed better liver function tests, a lower frequency of relapse and no marked withdrawal symptoms as evaluated using the Lesch typology system [132]. They concluded that the T-T allele could be protective against alcohol dependency and, specifically, hepatic toxicity and neurotoxic withdrawal [133]. Of course it is the neurotoxic effect that draws the attention of our discussion. At this juncture a logical sequel would be to consider the use of viral vector gene transduction be utilized to confer this T-T allele-­ associated protection upon those who suffer from alcohol abuse [134]. Studies could then be conducted to examine any effect of this manipulation upon alcoholic neuropathy.

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Miscellaneous Disulfiram Toxicity Ironically, one drug that has been used as an effective treatment for alcoholism also has the side effect of causing a peripheral neuropathy in and of itself. Disulfiram has been in use since the turn of the last century where it was used in the vulcanization of rubber. Workers exposed to the molecule were observed to demonstrate an intolerance to ethanol with the almost immediate onset of headache, drowsiness, dry mouth, dizziness, fatigue, and other signs of the classic hangover. This observation led to the clinical use of disulfiram (Antabuse®) as a deterrent therapy for chronic alcoholism as early as 1951 [135, 136]. Disulfiram toxicity occurs in roughly 1 in 15,000 patients being treated for chronic alcoholism who receive the drug [137, 138]. Its onset is rapid [136, 138–140], and it has been variably characterized by the acute development of neuropathy with burning dysesthesias, numbness, and pain on the plantar aspects of the feet and legs beneath the knees; [138, 141] it is also characterized by loss of the Achilles tendon reflex, and tactile pin-prick and vibratory sensory impairment in a stocking distribution [138]. The culprit in the development of disulfiram toxicity is believed to be its toxic metabolite, carbon disulfide (CS2) neurotoxicity in a murine model in 2000. They found that mice exposed to CS2 had abnormal cross-linking of erythrocyte spectrum. They proposed that a similar crosslinking event occurred in neurofilament proteins in a rat model in a time and dose-­ dependent manner and that this interaction contributed to axonal swelling [142]. This swelling is believed caused by the growing aggregate of cross-linked neurofilament proteins that cannot pass through a narrow node of Ranvier. The result is severe hindrance or complete cessation of axonal flow, inability to deliver important nutrients and subsequent neuronal ischemia, inflammation and cell death [143]. The appearance on pathologic exam, axonal degradation, is thus similar to that of ethanol-­induced neuropathy and thus the diagnosis may better be determined via examination of temporal relationships between disulfiram administration and ethanol use/abstinence. Treatment of disulfiram neuropathy may be attempted with such general neuropathy targeting drugs as gabapentin, [136] but in general, the best and most logical course of treatment is cessation of disulfiram administration. This latter course has been met with symptomatic improve in days to weeks; [136, 139, 140, 143] but full recovery is not always achieved and it has been suggested that disulfiram neuropathy is being underdiagnosed [141].

Summary This chapter describes the prevalence, risk factors, molecular pathology and management of alcoholic neuropathy. Quantity, duration and consistency of alcohol ingestion are known determinants of the incidence and severity of this neuropathy; these exist in concert with demographic factors such as gender and age. This neuropathy affects both supraspinal (central) and peripheral nervous systems but clinical manifestations are more likely due to peripheral neuropathy as the blood brain barrier delays supraspinal effects.

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At the supraspinal level, signal transduction and direct damage to the cell membrane by ethanol are implicated. The constellation of peripheral neuropathy includes autonomic dysfunction. Studies examining current perception threshold, sympathetic skin response, sweating patterns point to lesions in the efferent pathway. Symptoms present in a symmetrical distribution, although sensory and motor derangements are dependent on the degree of severity. The effects of ethanol are mediated through GABA mediated chloride channels, calcium channels, NMDA receptors dependent neurotransmitters as well as other excitatory amino acids. These mechanisms result in the blunting of excitatory pathways, long-term synaptic potentiation, potential chronification of pain and are suspected of playing a role in ethanol withdrawal. By inducing dopamine accumulation, ethanol causes a downstream desensitization to adenyl cyclase production which could result in physical dependence. Understanding these mechanisms presents interesting pharmacologic targets and clinically significant management strategies for alcoholism and its ensuing complications. This chapter also presents an examination of the relationship between acute and chronic alcohol intake, and neurologic derangements. Historically thiamine deficiency was incorrectly identified as the causative mechanism for alcoholic neuropathy, however this was due to the common occurrence of nutritional deficiency (including thiamine) in alcoholic patients. Although the ability to conduct rigorous clinical studies are limited by ethical considerations, several mechanisms of alcoholic neuropathy have been proposed.  These are  based upon clinical observation, anecdotal reports and bench research. These proposed mechanisms include activation of spinal cord microglia; pro-inflammatory cytokine mediated activation of protein kinase; activation of mGlu5 receptors in the spinal cord; activation of the sympathoadrenal and hypothalamo-­pituitary adrenal axis; and direct toxic effects. Acetaldehyde, the most toxic metabolite of ethanol, is implicated in disrupting multiple crucial hepatic functions. Reactive oxygen species appear to be involved in capsaicin induced pain from central sensitization. Many  neuropathic conditions overlap in symptomatology. Diagnosis  can be challenging and is dependent upon the patient’s substance history and findings on physical examination. The use of sodium channel blockers in the treatment of alcoholic neuropathy has been described in case reports and case series. Local anesthetics have shown promising effects although these are attributed to antiinflammatory and antinociceptive properties. Therapeutic agents such as benfotiamine (thiamine prodrug), and  free radical scavengers have been used to counter the proposed pathologic mechanisms. Although there remain unanswered questions regarding the pathogenesis of alcoholic neuropathy existing molecular based theories and ensuing potential novel therapeutics  offer some promise. These novel therapies do not necessarily target etiologic mechanisms but act through mechanisms that are used as treatments for neuropathies that share commonalities with alcoholic neuropathy, and thus could potentially prove effective. These warrant further study.

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117. Quintans JSS, Antoniolli AR, Almeida JRGS, et al. Natural products evaluated in neuropathic pain models - a systematic review. Basic Clin Pharmacol Toxicol. 2014;114(6):442–50. 118. Yan Y, Shapiro JI. The physiological and clinical importance of sodium potassium ATPase in cardiovascular diseases. Curr Opin Pharmacol. 2016;27:43–9. 119. Cherian DA, Peter T, Narayanan A, et al. Malondialdehyde as a marker of oxidative stress in periodontitis patients. J Pharm Bioallied Sci. 2019;11(Suppl 2):S297–300. 120. Khan AA, Alsahli MA, Rahmani AH.  Myeloperoxidase as an active disease biomarker: recent biochemical and pathological perspectives. Med Sci (Basel). 2018;6(2):33. 121. Raygude KS, Kandhare AD, Ghosh P, et  al. Evaluation of ameliorative effect of quercetin in experimental model of alcoholic neuropathy in rats. Inflammopharmacology. 2012;20(6):331–41. 122. Salehi B, Mishra AP, Nigam M, et al. Resveratrol: A double-edged sword in health benefits. Biomedicine. 2018;6(3):91. 123. Newaz MA, Nawal NN. Effect of gamma-tocotrienol on blood pressure, lipid peroxidation and total antioxidant status in spontaneously hypertensive rats (SHR). Clin Exp Hypertens. 1999;21(8):1297–313. 124. Hsieh TC, Wu JM. Suppression of cell proliferation and gene expression by combinatorial synergy of EGCG, resveratrol and gamma-tocotrienol in estrogen receptor-positive MCF-7 breast cancer cells. Int J Oncol. 2008;33(4):851–9. 125. Park GB, Kim YS, Lee HK, et  al. Endoplasmic reticulum stress-mediated apopto sis of EBV-­transformed B cells by cross-linking of CD70 is dependent upon generation of reactive oxygen species and activation of p38 MAPK and JNK pathway. J Immunol. 2010;185(12):7274–84. 126. Sun W, Wang Q, Chen B, et al. Gamma-tocotrienol-induced apoptosis in human gastric cancer SGC-7901 cells is associated with a suppression in mitogen-activated protein kinase signalling. Br J Nutr. 2008;99(6):1247–54. 127. Tiwari V, Kuhad A, Chopra K. Tocotrienol ameliorates behavioral and biochemical alterations in the rat model of alcoholic neuropathy. Pain. 2009;145(1–2):129–35. 128. Tiwari V, Kuhad A, Chopra K. Neuroprotective effect of vitamin e isoforms against chronic alcohol-induced peripheral neurotoxicity: possible involvement of oxidative-nitrodative stress. Phytother Res. 2012;26(11):1738–45. 129. Information, N.C.f.B., Epigallocatechin,CID=72277, in PubChem Database. 2020. 130. Tiwari V, Kuhad A, Chopra K. Downregulation of oxido-inflammatory cascade in alcoholic neuropathic pain by epigallocatechin-3-gallate. J Neurol. 2010;257:S66. 131. Cortese C, Motti C. MTHFR gene polymorphism, homocysteine and cardiovascular disease. Public Health Nutr. 2001;4(2B):493–7. 132. Schlaff G, Walter H, Lesch OM. The Lesch alcoholism typology - psychiatric and psychosocial treatment approaches. Ann Gastroenterol. 2011;24(2):89–97. 133. Saffroy R, Benyamina A, Pham P, et al. Protective effect against alcohol dependence of the thermolabile variant of MTHFR. Drug Alcohol Depend. 2008;96(1–2):30–6. 134. Tomanin R, Scarpa M. Why do we need new gene therapy viral vectors? Characteristics, limitations and future perspectives of viral vector transduction. Curr Gene Ther. 2004;4(4):357–72. 135. Kragh H.  From disulfiram to antabuse:the invention of a drug. Bull Hist Chem. 2008;33(2):82–8. 136. Layek AK, Ghosh S, Mukhopadhyay S, et al. A rare case of disulfiram-induced peripheral neuropathy. Indian J Psychiatry. 2014;56:S65. 137. Behan C, Lane A, Clarke M. Disulfiram induced peripheral neuropathy: between the devil and the deep blue sea. Ir J Psychol Med. 2007;24(3):115–6. 138. Vujisić S, Radulović L, Knežević-Apostolski S, et  al. Disulfiram-induced polyneurophaty. Vojnosanit Pregl. 2012;69(5):453–75.

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Uremic Neuropathy Anil Arekapudi and Daryl I. Smith

Introduction Uremia can result from profound glomerular dysfunction associated with disturbances in the tubular and endocrine functions of the kidney. This dysfunction leads to accumulation of toxic substances which alter the volume and composition of the body-fluid compartments along with abnormal levels of various hormones [1]. The Massry/Koch postulate of 1977 further identifies criteria to determine uremic toxins. These criteria include: chemical identification and characterization of the toxin; the ability to quantify the toxin in biological fluids; uremia-related toxin levels in biological fluids; a relationship between the level of the toxin in biological fluids and one or more of the manifestations of uremia; a reduction in the level of the toxin in biological fluids with a resultant amelioration of the uremic manifestation; and reproduction of the uremic manifestation in otherwise normal mammalian models when the toxin is administered to levels observed in uremia [2]. These toxins have a variety of physiochemical and pathobiological effects and function on a molecular and cellular level. It has been suggested that the toxins inhibit nerve fiber enzymes that are required for energy production, therefore leading to a depletion of energy [3]. Studies have shown that large nerve fibers are mostly affected by structure impairment of axons and myelin sheaths along with demyelination of axons [4–7]. Nodes of Ranvier are highly susceptible to energy deprivation within the axon as they demand more energy for impulse conduction and axonal transport [8]. They can be classified as small water soluble compounds, small protein bound A. Arekapudi Oakville Trafalgar Hospital, Oakville, ON, Canada Department of Anesthesia, McMaster University, Hamilton, ON, Canada D. I. Smith (*) University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_10

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compounds and middle molecules. An early description of the polyneuropathy associated with chronic renal failure was put forth by Bolton in 1980. He described a distal motor and sensory polyneuropathy comprised of segmental demyelination, axonal degeneration, and segmental remyelination. At the time of his description the nature of the uremic toxins and the mechanisms of injury were unknown. Bolton did go on to suggest that membrane dysfunction occurs which specifically involved the perineurium and the endoneurium, and thus the normally competent barrier between interstitial fluid and nerve, or between blood and nerve could now allow for uremic toxins to enter the endoneurium space and cause direct nerve damage [9].

Risk Factors There is a dearth of literature regarding specific risk factors for the development of uremic neuropathy. Underlying occult neuronal compromise may multiply the risk that such a patient may become symptomatic when subjected to the demyelinating effects of uremia, however these studies have yet to be performed. One study that did examine this risk was performed by Abu-Hegazy, et al., in 2010. It employed multivariate analysis to determine risk factors for the development of uremic neuropathy in young, renal transplant recipients. Acute rejection episodes, graft dysfunction, cumulative steroid dose and anemia were significant risk factors for the development of neuropathy [10]. Wittman, et al., iterated that uremia, and advanced glycation end-products with concomitant oxidative stress were triggering factors of the disease but presented no specific risk data [11].

Diagnosis of Uremic Neuropathy The prevalence of uremic polyneuropathy has been reported as between 60 and 100% in uremic patients [12]. For therapeutic direction and an indication of severity of subclinical and newly discovered disease, it is important to develop specific diagnostic tests. One study employed the cutaneous silent period (CSP), to determine the function of A-fibers. The CSP is the interruption in voluntary contraction which follows a strong electrical stimulation of a cutaneous nerve. The CSP is mediated by spinal modulation of the motor cortex and is believed to be a protective reflex [13]. Stosovic, et al., used neural electrophysiology in a novel way when they attempted to correlate certain parameters with individual mortality. They examined motor nerve conduction velocity (MCV); terminal latency (TL) and F wave latency of the peroneal nerv; and studied sensory nerve conduction velocity (SCV) of the sural nerve in 75 nondiabetic patients. They also evaluated hemodialysis modality (bicarbonate dialysis versus biocompatible membranes); and  Kt/V (a measure of the change in concentration of the dialyzer clearance of urea multiplied by “time”, t; divided by the volume of distribution of urea). And they also factored the presence or absence of ischemic heart disease and/or congestive heart failure. MCV was

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found to be a significant mortality risk predictor while SCV alone was related to the use of biocompatible membranes and severity of polyneuropathy [14]. In a study purposed to evaluate the function of A-fibers (large diameter, myelinated), randomly selected, thrice weekly hemodialysis patients were selected and tested against a control; group of age-matched healthy volunteers. A-delta nerve fiber function was measured using CSP. Mean CSP onset latency was significantly larger in the dialysis patients than in the normal group (p  60 milliliters per minute per 1.73 meters squared); the group used structured cognitive testing at baseline and at annual evaluations. They employed 19 cognitive tests. Their results showed an increased rate of cognitive decline associated with a lower GFR.  They found that after all demographic corrections were made, the increased rate of cognitive decline associated with a 15 milliliter per minute per 1.73 meters squared lower GFR was similar to the effect of being 3 years older at baseline. There were associated declines in semantic memory, episodic memory, and working memory. The group found that there was no impact on visuospatial abilities or perceptual speed [81, 82]. While this study elegantly showed the relationship of impaired cognition and renal function, it failed to demonstrate any true causative or mechanistic component. This was proposed earlier in 2002 when Kiernan, et al., zeroed in on serum potassium as critical to this impairment. They used an in vivo human model to examine multiple nerve excitability measurements and examined axonal membrane properties in the setting of chronic renal failure. Looking at several electrophysiology parameters using the median nerve at the wrist, they found that there were abnormalities in axonal excitability. Excitability parameters are the most sensitive to membrane potential and abnormalities. And each abnormality was reduced following hemodialysis and patients with normal axonal resting potentials had normal serum potassium. They concluded that nerves are depolarized in many patients with CRF and the depolarization is due to potassium [83]. This finding is consistent with in vitro reports of the role of potassium in

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neuronal excitability and potential excitotoxicity [40, 41, 43, 83]. Renal  replacement therapy appears to be the most promising therapeutic approach. Other pharmacologic interventions have been proposed and while most (gabapentinoids, tricyclic antidepressants, and duloxetine) target neuropathic pain primarily, the thiamine derivative benfotiamine has been shown, in a murine model of Alzheimer’s disease, to enhance spatial memory. The drug was also shown to reduce amyloid plaque numbers and phosphorylated  tau levels in cortical areas of the transgenic mice brains [11, 84]. Later, Wittman, et  al. (2015) iterated that uremia, and advanced glycation end-products with concomitant oxidative stress were triggering factors and that treatment with benfotiamine in addition to first-line drugs such as gabapentin, pregabalin, tricyclic antidepressants and duloxetine should be considered [11]. Benfotiamine  specifically targets  inflammation as a result of oxidative stress and this appears to be a direct mechanistic therapy.

Treatment Treatment of uremic neuropathy is predominantly focused upon the management of the downstream physiologic effects to elevated serum uremic compounds. The ultimate therapies for uremia are chronic hemodialysis or peritoneal dialysis and successful renal transplantation [85]. In the absence of these therapies, either because of non-indication or unavailability, other interventions have been examined. The more conventional treatments of uremic neuropathy have  been discussed above in the individual sections dealing with the specific presentations of uremic neuropathy, i.e., cognitive impairment, pruritus, etc. In those sections we find the usual “suspects” found in most therapeutic regimens for neuropathic pain of all origins: gabapentinoids, tricyclic antidepressants, and duloxetine This section emphasizes interventions that we believe possess a more mechanistic targeting.

Zinc Uremia may lead to derangements of the micro element, zinc. This derangement in and of itself triggers some of the complications of uremia [86]. There are more than 120 zinc-dependent enzymes and the symptoms of zinc deficiency can stimulate deficiencies of amino acids, lipid acids, vitamins and can also mimic symptoms of chronic renal insufficiency . This is most likely the result of the development of an oxidative stress state in which an impairment of the balance between free radical formation and the antioxidant capacity of the patient exists. Several molecular derangements can occur as a result. These include lipid peroxidation and damage to DNA and various proteins. Defense mechanisms are in place to prevent the effects of oxidative stress. The common functions of these mechanisms is the capture and the inhibition of the formation of free radicals and the chelation of ion metals that catalyze free radical reactions. The myriad of trace elements are critical components of antioxidant enzymes involved in antioxidant mechanisms. Zinc, along with

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manganese and copper are part of the superoxide dismutase enzyme system which catalyze the superoxide anion dismutation into hydrogen peroxide and oxygen. Antioxidant enzyme activity is critically dependent upon trace elements, such as zinc, and the deficiency of these elements is a critical component in several disease processes and, more specifically, uremic neuropathy [87].

Retigabine Retigabine opens neuronal voltage-gated potassium channels and causes resting membrane potential stabilization, neuronal subthreshold excitability control and anticonvulsant effects. Two phase III trials (RESTORE-1 and RESTORE-2) have demonstrated the clinical efficacy of adjunctive oral Retigabine in adults with inadequately controlled partial-onset seizures [88]. A neuroprotective role for the drug was observed by Nodera, et al., when the group determined that the drug, a Kv7 channel agonist was effective in the treatment of cisplatin-induced peripheral neuropathy [89]. Krishnan, et  al., then applied threshold tracking to a second, toxic neuropathy (uremic neuropathy) and asserted that retigabine may potentially prove efficacious as an analgesic in this syndrome [65, 90].

Flumarizine The selective calcium entry blocker flumarizine has shown promise in the treatment of uremic neuropathy, albeit the form of disease caused by toxicity from the chemotherapeutic agent cisplatin [91, 92]. It also exhibits histamine H1 blocking activity. Flumarizine has been shown to possess non-selective blocking of voltage-­dependent Ca2+ and Na+ channel. Golumbek, et  al., examined the effects of flumarizine on spontaneous post-synaptic currents using patch-clamp electrophysiology. They showed that the drug attenuated the amplitude of spontaneous post-synaptic currents in acute brain slices using a murine model. In the presence of high extracellular potassium flumarizine reduced both the amplitude and the frequency of post-synaptic currents [93]. The efficacy of flumarizine may be due to enhanced neuronal stability and protection from potassium-induced excitotoxicity. Muthuraman, et al., studied flumarizine as a possible treatment for uremic neuropathy in rats. The group found that the drug attenuated the cisplatin-induced tissue biochemical changes (total calcium, superoxide, DNA, transketolase activity, and myeloperoxidase activity) in a dose dependent manner. More precisely cis-­ platin causes the accumulation of neurotoxins which lead to free radical generation, calcium overload, DNA breakdown, and alteration of transketolase and myeloperoxidase activity. These events are associated with neuropathic pain in a murine model. This cascade is initiated by calcium-induced activation of calcium binding

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protein and the generation of free radicals from mitochondria [94], which leads to the development of neuropathic pain and most importantly axonal degeneration. Flumarizine possesses free radical scavenging ability via the closing of calcium channels. Its  therapeutic value in treating uremic neuropathy may  result from its anti-oxidant and anti-inflammatory actions [92].

Alpha-Lipoic Acid Alpha lipoic acid (Fig.  4) is a naturally occurring micronutrient synthesized by humans but in relatively small amounts. It acts as a free radical scavenger and assists in repairing oxidative damage and regenerates endogenous antioxidants such as glutathione as well as vitamin C and vitamin E. It also chelates metals and promotes glutathione synthesis [95]. Alpha-lipoic acid is absorbed from the small intestine and distributed to the liver via the portal system and the systemic circulation. It is found in various body tissues, intracellularly, intramitochonrially, and extracellularly [96]. The impact of peritoneal nerve injury in uremic neuropathy patients was addressed by Potic, et  al., in 2010. They used electromyographic testing of four peripheral nerves. The medications tested were B vitamins, antidepressants (sertraline), and alpha-lipoic acid. When queried using the McGill test and the Numerical Rating Scale for pain assessment, alpha-lipoic acid was found to be superior by virtue of providing pain relief for longer than six months [97].

Gangliosides Gangliosides are glycosphingolipids (GSL), are found in tissues and body fluids, and are most abundantly expressed in the nervous system [98]. The synthesis of GSL is generally initiated in the endoplasmic reticulum and completed in the Golgi apparatus, followed by transportation to the plasma membrane surface as an integral component of the structure [98]. In addition to plasma membranes, GSL are present on nuclear membranes and are believed to play critical roles in modulating

Fig. 4  Alpha-Lipoic Acid

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intracellular calcium homeostasis and the ensuing cellular functions [99]. Gangliosides of the a-series of gangliotetraose gangliosides (GM1, GD1a), occur in the nuclear envelope and the endonuclear compartment. GM1, in the inner membrane of the nuclear envelope (NE), potentiates the Na (+) Ca (2+) exchanger by virtue of its tight proximity to this molecule and thus contributes to intracellular calcium regulation. This relationship is neuroprotective since absence or inactivation of the complex rendered cells vulnerable to cell death via apoptotic processes [99]. Anti-ganglioside antibodies initiate immune responses against peripheral nerves and eventually against peripheral nerves with inevitable failure in peripheral nerve regeneration. Lindner, et al., examined the clinical usefulness of gangliosides in patients suffering from neurological complications of the chronic and insufficiency on periodic hemodialysis treatment. Intramuscular injections of gangliosides (20 milligrams) were administered daily for 60 days and neurological (subjective and objective) and instrument examinations were performed. Patients who received ganglioside therapy showed significant improvement when compared to patients in the control group who received placebo [100]. This work is dated, however, and we could find no further, relevant recent studies.

Benfotiamine An indirect course of examination led to the consideration of benfotiamine in the formation of reactive oxygen species. Transketolase is the enzyme responsible for the prevention of accumulation of toxic glucose metabolites, the advanced glycation end products (AGE) [101]. The enzyme requires thiamine as a cofactor. Benfotiamine (Fig. 5) is a lipophilic thiamine prodrug and has been shown to prevent retinal and renal changes in animal studies. More importantly, benfotiamine prevented oxidative stress induced by the uremic toxin indoxyl sulfate as well as mutagen-4-­ nitroquinolone-­1-oxide (NQO) and angiotensin II.  Benfotiamine showed a direct

Fig. 5 Benfotiamine

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antioxidant effect in cell-free preparation [102]. The potential benefit of this prodrug in uremic neuropathy lies not only in the fact that it is protective against indoxyl sulfate but potentially against another toxic uremic compound, methylglyoxal, which also causes injury via oxidative stress. Studies are needed which examine efficacy of benfotiamine against uremic compound induced neuropathy to discern its efficacy as a potentially viable therapeutic intervention; and to further define the mechanism by which these compounds cause neurological injury [102].

Summary Approximately 60–100% of patients with uremia caused by glomerular dysfunction have signs and symptoms of uremic neuropathy. In post-renal transplant patients, cumulative steroid use, graft dysfunction and acute rejection episodes were commonly identified risk factors for developing uremic neuropathy. Uremia can lead to the accumulation of toxins such as guanidino compounds, creatine, creatol, methylglyoxal, guanidine, potassium and hyperparathyroidism. Because of functional cross talk between the kidney and brain via anatomic, vasoregulatory, humoral and non humoral bi-directional pathways, uremia may trigger the development of central and peripheral nervous system disturbances. Uremic encephalopathy, seizures, stroke, movement disorders, visual deterioration, impaired cognitive function and sleep disorders manifest centrally while polyneuropathy and carpal tunnel syndrome is commonly seen in the periphery. Though there is no absolute test to diagnose the severity of uremic neuropathy cutaneous silent period testing appears to be a reliable objective way. Chronic hemodialysis, peritoneal dialysis and renal transplant are definitive treatment options for uremia. Relatively novel therapies such as zinc, retigabine, flumarizine, alpha-lipoic acid, gangliosides, and benfotiamine help to mitigate or improve the symptoms by various mechanisms. These require further critical examination in both the basic science and in the clinical research settings.

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Perfussion-Related Neuropathies Amie Hoefnagel, Oscar Alam-Mendez, and Michael Ibrahim

Cuban Epidemic Neuropathy The Cuban Epidemic Neuropathy was rare manifestation of an optic and peripheral neuropathy that affected the country of Cuba in the early 1990s. From late 1991 to January 14, 1994 the Cuban Ministry of Public Health reported more than 50,863 cases [1], during a period that parallels with an abrupt economic decline of the country due to the US economic embargo and the fall of the Soviet Union [1, 3]. The primary cause of Cuban Neuropathy is unknown. Among the possible reasons a nutritional deficiency and lifestyles producuced from the country’s socioeconomic situation at that time appear to play a key role in the pathogenesis. Other hypothesis like inflammation, central nervous system degeneration, or viral infection are still on debate. The most important risk factor associated to this pathology was cigar smoking, increasing the likelihood by 34 times when compared with non-smoking subjects; but only when the cigar consumption was greater than four cigars daily. Other risk factor were high alcohol and casssava (a tubercle that contains variable amounts of cyanide) consumption, age 45–65  years old, and low intake of food containing B-vitamins [1, 2]. On the other hand, high consumption of to animal proteins or fat,

A. Hoefnagel (*) Department of Anesthesiology, University of Florida College of Medicine, Jacksonville, FL, USA e-mail: [email protected] O. Alam-Mendez University of Mississippi Medical Center, Jackson, MS, USA e-mail: [email protected] M. Ibrahim University of Florida College of Medicine, Jacksonville, FL, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_11

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and B-complex vitamins notably vitamin B12, riboflavin, niacin, and pyridoxine; significantly decreased the risk developing Cuban Neuropathy [2]. Two distinctive clinical presentation were reported: an opic and a peripheral form of neuropathy. Among all cases reported, 52% developed the optic neuropathy form and 48% peripheral neuropathy [3]. The optical neuropathy was characterized by a subacute onset of decreased visual acuity and color vision, central scotomas, and loss of papillomacular-bundle fibers [1]. The peripheral neuropathy was manifested as a dorsolateral myeloneuropathy with sensory deficiency and posterior cord involvement: hypoesthesia to pinprick, light touch and vibration; bilateral paresia and diminished reflexes in lower extremities; and in some cases, autonomic affectation like neurogenic bladder [1, 3]. The most widely accepted cause the Cuban Epidemic Neuropathy is a combination of high smoking, alcohol, and cassava consumption, paired with a low intake of Vitamin B complex. Vitamin B12 (cyanocobalamin) and B9 (folic acid) play different and important roles in cell turnover, managing energy substrates, and also in the metabolism toxic substance. Deficiencies of these vitamins could result in an accumulation of harmful byproducts like cyanide and fomarate [4]. Cuba, well known for its cigars production and a high use of tobacco products among the population, therfore is primed for this neuropathy. Due to the crisis in Cuba in the early 90s, the availability for meat, oils, dairy products, and commercial rum was decreased or rationed. There was an increased market for a methanol-contained home brewed rum. Methanol is metabolized to fomarate via formaldehyde. Fomarate is a direct inhibitor of oxidative phosphorylation, which can lead to a metabolic acidosis, visual toxicity and coma when it raises to toxic levels [5]. Fomarate is metabolized to carbon dioxide and water in the presence of folic acid. Inhibition of the mitochondrial electron transport by toxic levels of cyanide or fomarate ultimately will lead to a decreased cellular energy, impaired axonal transport and ultimately will result in axonal degeneration. These results are compatible with a nutritional, toxic, or metabolic origin, and ruling out an inflammatory etiology [5], further supporting the above theory on the etiology of Cuban Epidemic Neuropathy. In the first quarter of 1993 the Ministry of public health in Cuba initiated a campaign to fight these vitamin deficiencies. Oral multivitamins supplements were distributed to the general population [5, 6]. Symptoms improved within a week of administration [6], and the incidence of Cuban Epidemic Neuropathy decreased significantly after the program initiation. No deaths were reported from this epidemic [3].

Ischemic Monomelic Neuropathy Ischemic monomelic neuropathy (IMN) as the name implies, it is an entity that presents with arterial insufficiency in one extremity that causes a selective nerve dysfunction. It was first described by Wilbourn et al. in 1983 [7] and is a disabling complication produced by hemodynamic changes following hemodialysis access

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such as arteriovenous fistula (AVF) in the upper extremity [8]. The fistula can create a steal phenomenon that affects exclusively distal nerves and leads to a multiple axonal loss neuropathy [9, 10] without overt signs of ischemia: diminished/absent pulses, pallor, cold extremity, delayed capillary refill, or tissue necrosis. The incidence of IMN is not well established and the syndrome is often underdiagnosed. Incidence varies with patient’s comorbidities and location or type of the arteriovenous communication (fistula or graft). The most important risk factor associated with IMN is diabetes, but other risks include: stenotic or occlusive arterial disease, neuropathic diseases, calcifying sclerosis, atherosclerotic disease, and female sex [9, 11]. Proximal fistulas have an increased incidence compared to more distal ones [9] without a distinct etiology for this observation. Arteriovenous grafts are morelikely to quickly develop IMN compared to AVF because grafts creates a greater physiologic steal phenomenon (91% for AVGs vs 73% for AVFs) [12]. The steal phenomenon occurs when there is a redirection of blood flow following a pressure gradient from a high pressure state to a lower pressure system. Well known examples of steal phenomenon can be seen in a stenotic lesion of the subclavian artery, which produces a retrograde blood flow in the vertebral artery to the ipsilateral arm (subclavian steal phenomenon); or at the coronary circulation, when blood flow is redirected away from a stenotic lesion in the presence of a coronary vasodilator (coronary steal syndrome). The same principle applies to arterial blood flow after a AVF creation. The blood flow is redirected following the path of less resistance into the venous circulation, creating a hypoperfusion to the distal arterial circulation. This hypoperfusion creates a sensory/motor impairment without tissue necrosis [13]. Patients with IMN experience acute pain, paresthesia and motor weakness on the affected limb distal to the AVF. This typically occurs shortly after (minutes to hours) the operation [14] and is caused by an underfilling of the vasa nervorum [9, 10, 14] (a network of small diameter blood vessels that provide blood supply to nerves and ganglia). This decrease in perfusion selectively affects the nerves and results in anaerobic generation of lactate, subsequent acidosis and cellular swelling that compromise nerve perfusion [15]. Within minutes the lack of oxygen ceases the oxidative phosphorylation in the mitochondria stopping the adenosine triphosphate (ATP) production. The energy deficiency creates a dysfunction in the Na/K ATPase allowing electrolytes to shift along the cellular membrane following a gradient concentration: Potassium leaks rapidly from the intracellular compartment and sodium is drive into the cell creating cellular edema [16]. Extracellular concentration of calcium is greater than the intracellular concentration. Calcium homeostasis depends on the ATP production to prevent an increase of intracellular concentration. Energy is required to actively drive calcium from the cell, exchange it for sodium at the cell membrane (through Na/K ATPase) and to sequester calcium inside the endoplasmic reticulum [17]. The lack of ATP produces a great influx of calcium into the cell producing several reactions and further activates phospholipases that degrade cell membranes and increase the production of arachidonic acid leading to more edema, vasospasm and inflammation [17].

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The anaerobic metabolism product of mitochondrial dysfunction is lactate. Lactate can produce irreversible nerve tissue damage when levels are above 18–25 micromol/g [18]. The decreased pH activates Acid-Sensing Ion Channels (ASIC) that are proton-gated cation channels expressed in both central and peripheral nervous systems at cell body and at terminals of peripheral nociceptive neurons [18]. ASIC are epithelial Na + channel/degenerin (ENaC/DEG) family of cation channels expressed in the peripheral sensory neurons [19, 20]. When activated by an acidification product of extracellular protons they become permeable to Na+, evoking a propagation of an action potential to high-threshold unmyelinated C or myelinated A fibers. These nociceptive neurons have their cell bodies in the dorsal root ganglia which synapses with second-order neurons in the dorsal horn, principally in laminas I and V, which constitute the major output from the dorsal horn to the thalamus and brainstem though the spinothalamic and spinoreticulothalamic tracts respectively [20]. IMN is a rare complication which makes difficult the diagnose with sometimes delayed treatment. It can be clinically diagnosed: diabetic patient with an acute onset of pain and neurologic symptoms after access creation, without frank signs of hypoperfusion. The differential diagnosis includes complications from of axillary block, patient positioning, and functional deficit secondary to surgical trauma [21]. Although observation had been used as a treatment with reported improvement in symptoms; immediate closure of the access is mandatory in a patient diagnosed with IMN as this increases the probability of recovery and could led to partial or full recovery of motor and sensitive and motor function [22].

Venous Insufficiency Venous insufficiency is the failure of veins to adequately return the blood back to the heart, especially from the lower extremities. This condition carries significant negative physical, financial, and psychological implications; with 65% of patients having severe pain, 81% experiencing decreased mobility, and 100% with a negative impact in their work capacity [23]. According to the Vascular Disease Foundation, more than six million people are suffering from this disease and a half million are dealing with venous ulcers in the United States alone [24]. The veins in the lower extremity are divided in two different but interconnected groups: superficial and deep system according to their relation with the muscle fascia. Both systems are in constant communication by perforator veins, with the superficial veins draining into the deep ones. Their role is to serve as a blood reservoir and to return blood to the heart. To accomplish blood return, veins possess one-way bicuspid valves that allow forward flow and prevent retrograde blood flow promoted by gravity, particularly in the erect position; helped by muscle pumps, specially calf muscles [25]. Venous insufficiency occurs when there is a bicuspid valves dysfunction (in superficial, deep, or perforator veins) and the blood return is impaired with subsequent venous hypertension and blood stasis [26]. This increased pressure is

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exacerbated by prolonged standing and muscle pump dysfunction [27]. Normally, when pump muscles contract the blood is propelled forward and the venous pressure decreases. Valve dysfunction in the superficial system will show as tortuous dilated veins ascending in the leg with reflux when examined on doppler ultrasound, [26] which is caused by weakness in the vessel wall, direct injury, or hormonal changes [25]. In deep veins, valvular impotence increases the rate of progression of venous disease and it is often secondary to deep vein thrombosis [23]. Clinical signs of chronic vein insufficiency are: varicose veins, hyperpigmentation, lipodermatosclerosis, and venous ulceration; while the symptoms are more subtle and nonspecific: leg fatigue, discomfort, heaviness and most important acute-­ on-­chronic dull pain [23]. There is a wide discrepancy between pain severity reported by patients and clinical findings. The pain can be absent in 45% of a varicose population [28] and in 45% of subjects with blood reflux [29]. The pain is thought to be secondary to two factors: wall distention and hypoxia/ inflamation which are a consequence of increased venous pressure. Interestingly, venous nociceptors are largely insensitive to mechanical activation by distension (a relevant clinical example is the arteriovenous fistula formation), meaning that venous dilatation is, to an extent, painless [30] where small diameter veins may be more prone to nociceptive stimuli [29, 30], and the most important source of pain should be hypoxia or inflamation. Sensory nerves fibers that innervate veins are located along the vessel wall and have their cell bodies in the dorsal root ganglia of the spinal cord. These nerve endings are nociceptors which are organized in two distinct collaterals: in the venous wall between the endothelial cell and smooth muscle of the tunica media (subendothelial), and in the perivenous space inside the connective tissue (perivascular) with close contact with the microcirculation [29]. These nociceptors are polymodal (one receptor can respond to different stimuli) [31]. A myelinated or C unmyelinated nerve fiber are responsible to generate painful signals when facing a mechanical, chemical, inflammation, or thermal stimuli such as: injury/stretch, hyperosmolar solution/inflammation, deep vein thrombosis, or cold infusion respectively [32]. Pain related to venous insufficiency is thought to be related to an inflammatory process secondary to local hypoxia, venous hypertension, and blood stasis. This lack of oxygen and adenosine triphosphate (ATP) production leads to an increase in the concentration of intracellular calcium which actives a reaction cascade that leads to an activation of phospholipase A2, release of proinflammatory mediators like prostaglandins E2 and D2, platelet activator factor, and leukotriene B4 [31, 32]. These chemotactic substance produces a local infiltration of leuko-endothelial cells: neutrophils, monocytes, macrophages, mast cells and lymphocytes T cells [30–32] which are the most important factor on initiation and maintenance of chronic inflammation by producing adhesion molecules, cytokines, and prothrombotic factors [31–33] and may harvest the bases for treatment. The inflammatory state produces several ligands that stimulates different receptor at the C unmyelinated and A myelinated nerve endings: voltage-gated sodium channels tetrodotoxin-2 (TTX2); acid sensitive ion channels (ASIC); and non-­ selective cation channels vanilloid receptor-1 (VR1) and ATP sensitive P2X

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purinoceptor 3 (P2X3) [31]. This nociceptors are responsible for the transduction, conduction, and transmission of painful stimulus to the thalamus and brainstem. Chronic inflammation gradually develop into the trophic changes of chronic venous disease. Such alteration can explain the decreased intensity reported by patients as the disease progresses, which is possibly related to the chronic ischemia. Patients experience a threshold elevation for thermal, tactile and vibration sensations due to loss of sensory axons [34, 35]. Supportive treatment measures are directed to decrease the venous hypertension by periodic leg elevation, avoidanc of prolonged standing, weight loss, the use of low adherent absorbent dressings, and external compression stocking. Although this measures may decrease symptoms, they do not prevent the progression of the disease [36]. Surgical intervention include: endovenous ablation, sclerotherapy, ligation, bypass or valve reconstruction of varicose veins. Ablation with laser or radiofrequency promotes a thrombotic occlusion and fibrosis inside the affected vein with the use of heat; while sclerotherapy achieve occlusion by chemical substance injection. Surgical ligation, bypass creation and valve reconstruction as their name imply, they are a vein separation from circulation, blood flow diversion and valve tightening respectively [23, 36]. Medical treatment tries to decrease the local inflammatory process and/or decrease the venous hypertension. Monoclonal antibodies targeting leukocytes adhesion molecules anti-VCAM or anti-ICAM interferes with the ability of leukocytes to adhere to the endothelium; they have shown to be effective in animal models, but not so promising in human, and carries significant side effects like neutropenia [30]. Micronized purified flavonoid fraction are venotonic medications with a partial reduction of adhesion molecule expression in leukocytes that lack the risk of neutropenia [37].

Sympathetic Denervation Neuropathy The sympathetic nervous system is part of the autonomic nervous system. Within the sympathetic nervous system there are two types of neurons that may be involved in signaling; namely pre-ganglionic and post-ganglionic neurons. At the synapses with the ganglia these neurons release either acetylcholine (activates nicotinic acetylcholine receptor on postganglionic neruons) or norepinephrine (activates adrenergic receptors in target tissues). Pain can be created by abnormal sympathetic nervous system function in the limbs, as is seen in millions of patients in the form of diabetic neuropathy. This is a long-term complication of type 1 and type 2 diabetes, with a variety of symptoms varied from mild to intractable pain that is generally resistant to treatment [38]. Diabetic peripheral neuropathy is a complex phenomenon, and sympathetic denvervation may only play a small role in it’s etiology (see Chap. 3 Diabetic Neuropathy). Patients with diabetic neuropathy often present with physical findings of decreased or absent ankle deep-tendon reflexes, decreased/absent sensation to touch, vibration, or temperature. Generally these signs are more pronounced in the lower

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extremities compared to the upper extremities. A decreased norepinephrine release into the bloodstream from local sympathetic nerve terminals has been demonstrated in patient with painful diabetic neuropathy, supporting the hypothesis that sypmathetic denervation plays a role in this pain syndrome [38]. In order to highlight the effect of the sympathetic nervous system on regional blood flow, a study by Tack et al. examined whether painful diabetic neuropathy is associated with abnormal sympathetic nervous function in affected limbs. Positron emission tomography (PET) scanning was used after intravenous injection of the sympathoneural imaging agent 6-[(18)F]-fluorodopamine to visualize sympathetic innervation and [(13)N]-ammonia to visualize local perfusion. The study compared non-neuropathic patients to diabetic patients with unilateral neuropathy. Comparisons were made between the involved limb and the non-involved limb, PET scanning revealed decreased flow using 6-[(18) F]- fluorodopamine derived radioactivity in patients with painful diabetic neuropathy as well evidence suggesting partial loss of sympathetic innervation [38]. The exact etiology by which sympathetic denervation leads to pain is not clear. It should also be noted that sympathetic denervation can be undertaken as a medical treatment for several disease sates, inluding sympathetic denvervation for cardiac arrythmias [39] and as a treatment for complex regional pain syndrome(CRPS) [40]. While sympathetic denervation may lead to pain syndromes as seen in diabetic neuropathy, it may also be used a treatment for other pain syndromes such as CRPS.

Hypertension-Related Neuropathy Chronic hypertension is known to create deleterious systemic effects on the human body. Many organs are affected by persistently elevated high blood pressure. There have been attempts to deliniate the relationship between hypertension of peripheral neuropathy, however a consistent correlation is lacking. A murcine model has been utilized to show changes in nerve composition differnces in hypertensive rats. Evaluation of the sciatic nerve in hypertensive rats showed that while the total number of nerve fibers was unchanged, there was a significant reduction the number of large mylenated fibers and an increase in small nerve fibers. Additonaly the mylenated areas were smaller in hypertensive animals. Furthermore, hypertension was shown to lead to increase in cell markers that are present after nerve transection [41, 42]. The role of hemodynamic factors regulating blood supply to peripheral nerves has been shown to be a major contributor to nerve damage [43]. Evidence from human and animal studies show that sensorimotor peripheral neuropathy is associated with reduced nerve perfusion, endoneurial hypoxia, and structural changes in nerve microvasculature. In fact, progressive atherosclerosis is thought to play a major role in creating these ischemic situations, as hypertension increases the production of atherosclerosis, this is especially true in diabetic patients [43]. Currently, the literature does not describe a clear relationship relationship between hypertension and diabetic peripheral neuropathy. Ozaki, et al in 2016 used

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a murine model to further examine if a correlation existed [42]. Specifically their goal was to analyze the effects of hypertension on diabetic neuropathy. They studied morphologic features of peripheral nerves in rats with hypertension. They divided male rats into two groups: alloxan-induced diabetic rats who received deoxycorticosterone acetate salt (DOCAS-salt) and non-diabetic rats who also received DOCA-­ salt. Sciatic, tibial (motor) and sural (sensory) nerves were then studied histomorphologically. Systolic blood pressure was maintained above 140 mmHg in both groups and endoneurial vessels in both groups showed endothelial hypertrophy and vessel lumen narrowing. Utilizing electron microscopic analysis, it was revealed that a duplication of the basal lamina surrounding the endothelium and pericytes of the endoneurial vessels, a lesion the group stated that was more frequent and severe in the diabetic group. Furthermore, morphometric analysis of the tibial nerve uncovered a shift to smaller fiber and myelin sizes in the diabetic group when compared to the control group. On the other hand, a different mechanism can be used to explain a unique hypertension mediated pain syndrome, which can be seen as chest pain in patients with hypertension, but without significant coronary artery disese. Arterial hypertension is often associated with a stiff aorta, produced as a result of collagen accumulation in the aortic wall. This relationship between increased collagen production and increased oxygen demand, especially during exercise, can cause exercise-induced chest pain, even in patients with normal coronary arteries. The presence of a stiff aorta allows for less distension, thereby increasing aortic wall tension, especially during exercise. Free amino-terminal pro-peptides of pro-collagen type I (PINP) can be used as an index of collagen synthesis and serum telopeptides of type I collagen (CITP) a measure of collagen degradation. While serum levels of pro-­ metalloproteinase-­1 (ProMMP-1) and its tissue inhibitor TIMP-1 can be used as indices of collagen turnover. It was found that patients with chest pain during exercise had significantly greater carotid-femoral pulse wave velocities (PWVc-f) compared to those without chest pain, also mean PINP levels were also greater [42]. Furthermore the PINP/CITP ratio was significantly higher in patients with chest pain compared to those without [44]. Thus, patients with arterial hypertension, even with normally appearing vasculature who experienced chest pain, had stiffer aortas when compared to those without chest pain. The thought is that there is increased wall tension in stiff aortas, which may stimulate aortic pain fibers and cause chest pain. The aortic adventitia contains pain fibers and aortic wall stretch may produce chest pain. Also aortic stiffness may be associated with lower diastolic pressure during exercise causing a decrease in subendocardial blood flow and possibly ischemic chest pain [44].

Hypotension-Related Neuropathy Systemic hypotension is known to cause a reduction in perfusion, potentially leading to ischemia and tissue damage. A resultant reduction in perfusion to organs which have a high oxygen demand is known to cause ischemia and tissue damage.

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However, does transient hypotension, such as orthostatic hypotension, cause any related neuropathy? We look at the example of “coat-hanger ache“, which is brought on by orthostatic hypotension causing neck pain radiating to the occipital region of the skull and the shoulders. This has been attributed to muscle hypoperfusion/ischemia in the presence of systemic hypotension in the upright position [45]. One study utilized velocity recovery cycles (VRC) of muscle action potentials to investigate muscle membrane function, where the changes in conduction velocity of a muscle action potential is a function of the interstimulus interval after a conditioning stimulus. The literature shows that patients with orthostatic hypotension and a positive history of coat-hanger ache had increasingly longer relative refractory periods, because the became progressively polarized, and a shift of the VRC curve right and upwards which is similar to healthy subjects during limb ischemia. This was attributed to membrane depolarization, which is known to reduce the amount of available sodium channels, so refractoriness increases and depolarizing afterpotential is reduced [45]. This resulted in the conclusion that the drop in perfusion pressure due to orthostatic hypotension was sufficient enough to cause ischemia. This ischemic pain was due to the combined action on the intramuscular nerve fibers of lactic acid and ATP released when ischemic muscle is activated. It has been shown that active ischemic muscles release ATP, which increases the sensitivity to lactic acid of acid-­ sensing ion channel number 3 (ASIC3) channels on nociceptors [44].

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Pressure-Induced Neuropathy and Treatments Daryl I. Smith, Syed Reefat Aziz, Stacey Umeozulu, and Hai Tran

Introduction Pressure-induced neuropathy (PIN) while implicated in such disease states as carpal tunnel syndrome, cubital tunnel syndrome; crush injury and compartment syndrome is also the result of iatrogenic causes such as improper positioning and padding during surgical procedures and injection overpressure during the performance of peripheral and central nerve blocks. Thus, PIN is in large part a disease of mechanotransduction. The purpose of this  chapter is to examine the specific molecular mechanisms involved in sensitization of mechanoreceptors; how these mechanisms cause the transition to sustained nociceptive input into the central nervous system; the time course of this evolution to chronic or neuropathic pain; and, finally, examine pathway sites at which specific interventions (either extant or hypothesized) may be executed to effect therapeutic benefit in this disease process. The evolutionary pattern of work on this subject dictates that we divide the discussion into two sections. The first examines basic science breakthroughs in the understanding of the involved molecular pathways. The second looks at observations in the clinical settings based upon insights that indicate previously unnoticed molecular mechanisms in the human model. D. I. Smith (*) University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA e-mail: [email protected] S. R. Aziz University of Rochester Medical Center, Department of Anesthesiology, Rochester, NY, USA S. Umeozulu Xavier University of Louisiana, New Orleans, LA, USA H. Tran URMC Strong Memorial Hospital, Department of Anesthesiology and Perioperative Medicine, Rochester, NY, USA © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_12

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The molecular mechanisms by which pressure-induced neuropathies are caused have been speculated upon since the Double Crush phenomenon was described by Upton and McComas in 1973 [1–3]. We still fail to understand this syndrome in its entirety and as a result we have been unable to provide cause-specific prophylaxis against and treatments of this malady. This  chapter will identify and discuss the proposed molecular mechanisms of pressure induced neuropathy. We will examine the basic sciences literature in order to find improvement in the understanding of the mechanism of development of pressure induced neuropathy on the molecular level. We will review models which specifically employ compressive techniques and the aberrant pathways that ensue. Finally, in this retrospective examination, we look back over the past 10 years at therapeutic developments that have targeted this syndrome and identify novel or as yet clinically untested therapeutic interventions that may prove valuable in a future clinical research setting.

Background The occurrence of PIN has led to guidelines of what defines overpressure, or what level of pressure places neural tissue at risk. While there is also a time function involved in the development of pressure induced neural injury, this chapter will focus upon the pressure component since there seems to be an inverse relationship between the time and pressure necessary to cause the injury once the critical pressure threshold has been crossed. Early studies of iatrogenically caused pressure injury that implicated high injection pressures in the development of neural injury were confounded by the use of vasoconstrictors in the local anesthetic formulation [4–6] and by the assumption that increased injection pressures necessarily indicated intraneural injection. In the study by Kapur they found that both intraneural injection and perineural injections could generate pressures less than 12 psi [6]. Is the corollary to this, then, that intraneural as well as extraneural injections may cause elevated peak pressures? The results of the Kapur study also showed that at the beginning of the injection both groups had a higher pressure, an event they referred to as “opening” pressure. This was followed by a lower pressure throughout the remainder of the injection. The group also found that the presence of high injection pressure during intraneural application of local anesthetic determined the duration of the sensory motor deficit. Upon histologic examination of the pressure-injured canine sciatic nerve at 7 days following injection, they found myelin swelling caused by displaced axons, complete disintegration of some axons; and hypercellularity with an increase in number of Schwann cells and macrophages [6]. While the prevention of injection pressure neuronal injury is the ideal therapeutic goal, this does not eliminate the need for effective therapeutic options once the injury cascade has begun. In order to accomplish this, it is necessary to understand the important molecular mechanisms that constitute this injury. The purpose of this chapter gathers and examines pertinent up-to-date literature over the past 10  years based on basic science and clinical research.

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“Pressure-Induced Neuropathy and Resultant Pain” The mechanism by which pressure on neural tissue induces neuropathic pain is not clearly understood currently, but several pathways towards its development have been proposed. Work over the last 10 years summarizes much of the current proven theories regarding the molecular contributions to this process.

Animal Studies Tumor Compression PIN in the setting of tumor pressure on vibrissal pads [7] was studied in a murine model when Ono et al. injected Walker carcinoma 256 B-cells [8] at this site. While behavioral data (food intake) was examined in this study, the group also studied c-Fos expression in the medullary horn. While earlier studies indicated that Walker cells play a role in tumor metastasis via the production of free radicals which cause vascular endothelial corruption and subsequent tumor cell access to the circulation, the group looked primarily at tumor compression by examining time-to-contact with nerve trunks following inoculation. This contact was temporally related with behavioral changes, allodynia and thermal hyperplasia. Of greater note at the molecular level, was the increase in c-Fos immunoreactivity in the ipsilateral dorsal horn [9].

Mechanotransduction Channels The transient receptor potential vanilloid 4 (TRPV-4), while known to be important in mechanical hyperalgesia of a number of types, is especially important in pressure induced neuropathy by virtue of its interaction with stretch activated ion channels (SAC). In 2009, Alessandri-Haber et al. examined the interaction of TRPC1, TRPC6 and TRPV4 in the development of nociceptor sensitization. They employed a selective SAC inhibitor, GsMTx-4 to define and manipulate a final common pathway step in the development of sensitization. Their murine model (rat hindpaw) showed not only a reversal of chemically induced (injection of inflammatory mediators) mechanical hyperalgesia, but also the reversal of hyperalgesia induced by chronic constriction injury (CCI). TRPC1 and TRPC6 are two known SACs that are expressed in DRG neurons. They are frequently co-expressed with TRPV4. When oligodeoxynucleotides antisense (â) was introduced to TRPC1 and TRPC6, there was reversal of the hyperalgesia to both mechanical and hypotonic stimuli induced by inflammatory mediators. There was no change to the baseline nociceptive threshold. They concluded that SACs cooperate with TRPV4 channels to mediate hyperalgesia and primary afferent nociceptor sensitization [10]. Findings such as these lead to the consideration of whether SAC inhibitors can be instituted in clinical situations in which there is a risk of compressive injury to peripheral nerves.

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The role of transduction molecules was also studied by Tsunozaki and Bautista in 2009. In this work the group determined that there was an intrinsic difficulty in creating accurate and specific models to study these molecules since there is a wide diversity of neuronal subtypes that detect a variety of mechanical stimuli. They posed the question of whether there is a transduction molecule that is common to multiple neuronal types or whether there are multiple neuronal types that are multiple mechanical transducers [11]. Currently there are three classes of ion channels that have been implicated in mammalian somatosensory mechanotransduction. Degenerin/ Epithelial sodium channels (DEG/ENaC); the aforementioned TRP channels; and two-pore potassium channels (KCNK). For touch responses to occur DEG/ENaC subunits and accessory proteins such as the mechanosensory abnormality 2 protein (MEC-2) protein which contains a stomatin-domain, and the paraoxonase-­ like, MEC-6 protein are required. Both proteins greatly increase channel activity (by 30–40 fold) when co-expressed with an activated version of MEC-4 in the Xenopus laevis oocyte model [12]. In humans the MEC-6-like proteins, paraoxonase 1 and paraoxonase 3 are believed to regulate cholesterol oxidation in high density lipoproteins. MEC-2 and podocin bind to cholesterol and a mutation which lowers MEC-2 binding to cholesterol renders animals more insensitive to touch when cholesterol levels are reduced [12]. In mammals the MEC-2 homolog stomatin-like protein 3 (SLP3) is necessary for mechanosensitivity in low-­threshold Aβ and Aδ fibers. This is not the case in C-fibers [11]. Of the TRP family of ion channels as mechanotransduction channels, TRPA1 has received the most attention [13]. Genetic knockout studies using single-fiber recording showed that TRPA1 knockout animals have reduced responses to mechanical stimuli in C-fibers and slowly adapting Aβ fibers [14]. Pharmacologic blockade of TRPA1 with the selective antagonist, HC-030031, diminished mechanical responses in C-fibers but not in TRPV1-contaning neurons. This result indicated that functional TRPA1 at sensory afferent terminals is required for responsiveness to mechanical stimuli [15]. The third class of ion channels implicated in mammalian somatosensory mechanotransduction is the two-pore potassium channel class (KCNK). These channels are widely expressed and they are activated by mechanical and thermal stimuli, protons, fatty acids, phospholipids; and local and volatile anesthetics. Several KCNK subunits are expressed in somatosensory neurons with KCNK2 activated by heat, osmotic stretch and pressure applied to membrane patches. In genetic studies, KCNK2-deficient mice displayed enhanced sensitivity to heat and mechanical stimuli; but only normal responses to severe mechanical pressure applied to the hindpaw [16]. This relationship and the potential for l potassium channel opener use in suggest that they might represent in neuropathic pain treatment context was iterated in a 2016 review by Busserolles. Another KCNK channel subtype implicated in the mechanotransduction model is KCNK18 (TRESK). The role of this subtype involves the regulation of resting potentials of somatosensory neurons [17] to the extent that in the KCNK 18 knockout murine model cellular excitability is significantly augmented. This leads us to wonder whether manipulation of KCNK can be accomplished such that we can limit the excitotoxicity that results from pressure induced neuronal injury. These

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relationships revolving around KCNK and related potassium channel openers and the suggestion that they might represent a viable treatment option in neuropathic pain syndromes treatment context was iterated in a 2016 review by Busserolles [18]. Mechanotransduction was revisited in 2011 by Delmas et  al. The group discussed the advent of functional assays that will provide insights into the molecular identity of mechanotransducer channels. This restated iterated the Tsunozaki and Bautista work [11] and added the acid-sensing channels. The acid-sensing channels (ASIC) belong to the proton- gated subgroup of the Degenerin-epithelial sodium channel family of cation channels. There are three ASIC family subgroups expressed in peripheral mechanoreceptors and nociceptors (ASIC1, ASIC2, and ASIC3). While the ASIC1A subgroup is implicated in the mechanical sensitivity of afferents innervating the gut; ASIC2 knockout mice have a decreased sensitivity of rapidly adapting cutaneous low threshold mechanoreceptors. The ASIC3 provides what is potentially the most fascinating mechanoreceptor consideration at least from a pathophysiologic standpoint. The knockout of ASIC3 in the murine model produces a reduction in mechanosensitivity in visceral afferents and reduces the response of cutaneous high threshold mechanoreceptors to noxious stimuli. This implies the ASIC3 is critical, at least in the murine model, to the initiation and maintenance of mechanosensitivity and leads us to speculate upon the degree of contribution of this excitotoxicity in both murine and human settings (Fig. 1) [19].

Hypotonic cell swelling

Shear stress

Mechanical driven positive pressure

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Fig. 1  In this image adapted from Delmas, a cartoon depicts changes secondary to mechanotransduction: shear stress, hypotonic cell swelling, stretch of a patch membrane, motor-driven positive pressure

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Fig. 2  General schematic representation of Aβ, C, and Aδ mechano- and polymodal nociceptors. In the quiescent condition, (a), the channel domains remain in the closed state. Membrane stretch (bold arrow) pulls the channel domains apart (b) and the open state results which allows ion flow (small arrows)

The models which best represent the injection insult are the shear stress and mechanically driven positive pressure models. The specific nerve fibers that are most likely to play critical roles in these insults are Aβ (skin stretch, Ruffini corpuscle); C and Aδ fibers as mechano- and polymodal nociceptors (Fig. 2). Further illustration is again adapted from the work of Delmas in which a cytoplasmic domain which is bound to membrane phospholipids, cytoskeletal elements, or an associated protein. Membrane stretch pulls the channel domains apart and the open state results [19]. In a 2014 work by Chen et al., the group specifically targeted TRPV-4 for antagonism in exploring a potential therapy for the treatment of trigeminal neuralgia, a widely accepted PIN. Interestingly the group initiated the trigeminal neuropathic pain behavior in their murine model with the use of the chemical irritant, formalin. They found that TRPV-4 activated the kinases MEK-ERK in the trigeminal ganglion sensory neurons and that TRPA and TRPV channels co-contribute to the formalin trigeminal pain response. They concluded that TRPV4 antagonism may lead to novel therapies [20]. A fourth class of mechanically gated ion channels exists which permits dermal sensation of light touch, with some mechanoreceptors detecting nanometer-scale movements. These channels, also known as PIEZO channels, are regulated by

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Fig. 3  Mechanically gated ion or PIEZO channels which detect nanometer-scale movements. In image (b) the resting or closed state is represented. When a traction force, (a); or a pulsion force, (c), is applied the channels open and ionic flow occurs

stomatin-like protein-3 (STOML3), a requisite for normal mechanoreceptor function. Recent studies have explained the role of STOML3  in the modulation of PIEZO2 channels in mechanoreceptors and nociceptors in pathophysiologic conditions [21] (Fig. 3) The subsequent development of small molecules that act as inhibitors of STOML3 function and the finding that these molecules can alleviate hypersensitivity in experimental pain models, leads to possible consideration of the suitability of these STOML3 inhibitors in the clinical setting [21].

Glial Activation/Deactivation Studies-Murine Model The role of glial cells in trigeminal neuropathic pain was explored in a study which used the potent astroglial cell inhibitor fluoroacetate. In a murine model, pressure-­ based, inferior alveolar nerve injury was induced, and mechanical- and heat-related injury behavior was assessed in the presence of fluoroacetate and in the control setting. This group also assessed specific astroglial activation in the trigeminal spinal nucleus caudalis (Vc), Vc nociceptive neuronal activity and the expression of phosphorylated extracellular signal-regulated kinase (pERK) in the same nerve injury model. Fluoroacetate improved neuropathic pain behavior; caused a reduction in the increased number of pERK-like immunoreactive cells in Vc; and caused a reduction in the enhanced Vc nociceptive neuronal responses following high intensity skin stimulation. The administration of glutamine restored the enhanced responses [22]. This study suggests the importance of glial cell-derived glutamine release in the maintenance and possibly the development of compressive neuropathic pain. Glial targeting in the treatment consideration of neuropathic pain was further examined in a study involving the gabapentinoid, pregabalin. Here Rivat et al. used partial infraorbital nerve ligation in a murine model and induced persistent pain behaviors as well as morphologic changes in the brainstem. In a comparison of 21 days of treatment (placebo versus pregabalin) following partial ligation of the infraorbital nerve the group found that in light of induction of mechanical allodynia which began the day after the surgery, treatment with pregabalin significantly reduced mechanical allodynia. The allodynia was measured with von Frey filaments

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applied in IoN territory near the center of the vibrissa pad. In addition the group observed astrocyte activation in the ipsilateral caudal medulla on days 4, 8, 14, and 21 following surgical nerve ligation; observed microglia activation only on days 1 and 4; and a 14 day increase in NK1 expression. They concluded that pregabalin inhibits the activation of astrocytes and microglia; and that it inhibits the increase in NK1 which occurs a s a reaction to neural compression injury [23]. Another study which focused upon microglial cell hyperactivity in the setting of pressure induced neuropathy examined orofacial pain secondary to hyperalgesia following infraorbital nerve injury. Specifically, this work examined spatial organization of these cells in the trigeminal spinal subnucleus caudalis and the upper cervical spinal cord at the level of C1. The group found that the head-withdrawal threshold to non-noxious mechanical stimulation of the maxillary whisker pad skin was reduced following injury on days 1–14, an indicator of the relatively rapid development of post-insult hyperesthesia. They also noted that on the third post-­ insult day mechanical allodynia was clearly observed in the orofacial skin areas in the distribution of the first, second, and third branches of the trigeminal nerves. They also found evidence of microglial cells in the Vc and C1 on the third and seventh post-injury day. In addition a large number of phosphorylated extracellular signal-regulated kinases (pERK)-immunoreactive (IR) cells were observed in Vc and C1 along with a large number of hyperactive microglial cells in a similar wide areas in the distribution of the trigeminal nerve. Of note is the fact that activation of microglial cells in Vc and C1 area enhances neuronal activity in the early period following constriction injury. Also of interest is the group’s use of the tetracycline antibiotic minocycline to reduce the activation of microglial cells and the number of phosphorylated, immunoreactive cells and attenuate the development of mechanical allodynia in the rodent. In a human clinical model the use of minocycline in neuropathic pain has been controversial, and there has been no significantly different therapeutic effect in minocycline versus amitriptyline in the treatment of lumbar radicular pain [24] although the group strongly recommends further study in other human neuropathic pain models [25]. Further examinations of compressive nerve injury and the role of glial cells were conducted using blockade of the synthesis of the stimulatory neural transmitter, glutamate, in the cells of the trigeminal motor nucleus with the glutamine synthase inhibitor, methionine sulfoxamine (MSO). Again, using the infraorbital nerve ligation, CCI murine model, the group noted an increase in glutamine synthase activity, as well as an increase in amplitude and duration of the jaw opening reflex (JOR) (neuropathic pain behavior). After administration of MSO, the authors observed strong suppression of JOR amplitude as well as a decrease in JOR duration. Interestingly subsequent administration of glutamine reversed the effect of MSO on JOR amplitude and duration. The group concluded that the astroglial glutamate-­ glutamine shuttle mechanism is involved in the motor component of compressive nerve injury [26]. Tumor necrosis factor alpha (TNFα) as a mediator of compressive nerve injury was explored by Ma et al. The pre-existing knowledge that this molecule is increased in the setting of headache, neuropathic pain, periodontal and temporomandibular

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disease led this group to utilize TNFα receptor KO animals to examine TNFα dysregulation in generation and maintenance of chronic neuropathic pain. Using a murine model, microglial activation was analyzed using cytokine proteome profiles. In TNFα receptor KO mice there was a delay in contralateral whisker pad allodynia but not in wild type mice following trigeminal inflammatory compression (TIC). Further proteome profiling at 10 weeks following injury revealed that in TNFR1/2 KO mice there was a two-fold increase in TNFα, IL-1α, IL-5, IL-23, macrophage inflammatory protein-1β (MIP-1β), and granulocyte macrophage colony stimulating factor (GM-CSF). These changes were in comparison with findings in WT mice with TIC and the resultant hypersensitivity was reduced by p 38 mitogen-activated protein kinase inhibitor and the microglial inhibitor, minocycline. This group concluded that TNFα was integral to cytokine regulation and thus the role of cytokines in neurogenic and humorally mediated chronic neuropathic pain [27]. One of the key components of PIN pain is the resultant disruption of myelination. Neuregulin1 (Nrg1) is a peptide ligand which signals via the receptor tyrosine kinase ErbB3-ErbB2 heterodimer. When the heterodimer is formed it promotes Schwann cell development and remyelination after nerve injury. Sensory dysfunction occurs when ErbB receptor-initiated signaling in glial cells associated with myelinated or non-myelinated nerves allows conducting/uninterrupted sensory fibers to conduct through the damaged nerve alongside degenerating fibers. In this study the group created chronic constriction injury with two chromic gut ligatures loosely tied around the infraorbital nerve. Nerve exposure but no ligation was performed in the sham operation. Sensory dysfunction defined as thermal and mechanical hypersensitivity was monitored. Ma et  al. determined that in Nrg1 Tg (or Nrg1-deficient genotype) rats there was no difference in the first phase (2  week period following CCI-Ion surgery) when compared to wild type animals. In the transgenic animals this condition persisted for another 5–6 weeks; whereas in the WT population hypersensitivity developed at 2 weeks [28]. These results imply that the Neureglin 1- ErbB2/ErbB3 axis in the setting of nerve injury promotes glial, axonal and Schwann cell growth and increased responses to nociceptive stimuli after neural injury. The targeting of this axis appears to be important to the consideration of therapeutic options that might prove of value. It was found in a 2006 study by Atanasoski et al. that ErbB2 signaling was not essential to the process of myelin repair and neither was it essential to neuronal survival nor proliferation following nerve injury [29]. Based in part on this fact Ma et al. inhibited the ErbB2 component with the ErbB2-specific inhibitor lapitinib. This prevented injury-related Schwann cell development and remyelination and the post-injury conduction of sensory fibers through damaged nerves [28].

Chronic Constrictive Injury-Murine Model Pressure induced neuropathy is thought to be the characteristic pathway in trigeminal system pain. Michot et al., used a CCI model to examine the role of the calcitonin gene related protein (CGRP)-receptor in the development of constriction injury.

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They measured expression of the c-Fos proto-oncogene (immediate early gene c-fos) a molecular marker of neural activity; the cyclic AMP-dependent transcription factor mRNA (ATF-3 mRNA); and interleukin 6 (IL-6) mRNA in the presence of the CGRP receptor inhibitor BIBN4096BS during both sciatic and infraorbital nerve ligation. The results, a decrease in c-Fos expression and ATF-3 mRNA but not IL-6 mRNA, suggested that the development of hypersensitivity may be similar in two anatomically remote but physiologically similar types of pressure induced neuropathies. In addition, their work reinforces the value of these two markers of PIN [30]. Compressive neuropathy involving the head and neck was studied using a chronic constriction murine model of the infraorbital nerve and pain-related behavior was tested 8, 15, and 26 days following surgery. The presence of allodynia demonstrated as the response threshold to von Frey hair mechanical stimuli to the injured side was determined, and unitary recordings of the caudalis division of the spinal trigeminal nucleus (SP5C) were made. Wide dynamic range (WDR) and low threshold mechanoreceptor (LTM) neurons were identified based upon the response to tactile or noxious stimulation. The group found that post-injury only the WDR neurons increased their spontaneous activity. Both WDR and LTM neurons however increased their response to tactile stimulus. In addition on-off tactile response was followed in both groups by after discharges not observed in control groups. In addition response inhibition during paired-pulse stimulation was reduced after compressive nerve injury, i.e. CLI-IoN and immunohistochemical studies revealed a decrease in the immunoreactivity of the 65 kD isoform of the enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2, glutamate decarboxylase or glutamic acid decarboxylase (GAD65). This activity was most marked in laminae I and II and the authors concluded that following the compression (CCI-IoN) there was suppression of the inhibitory circuits in the sensory trigeminal nuclei [31]. By way of the negation concept allodynia develops, i.e. there is a positive or excitatory effect on the nociceptive impulse. With inhibition allodynia may result. In a work that emphasized mechanism-based therapies for neuropathic pain, Pradhan et al. sought to determine whether treatment based upon etiology or behavioral endpoint (symptom) was most efficacious. This study used the CCI construct in a murine model of neuropathic pain. The group then assessed four types of evoked stimuli: heat, pressure, acetone cooling, and punctate mechanical. They then examined heat hyperalgesia and mechanical hyperalgesia across etiologies using the spinal nerve ligation model. They found that the two models had different temporal characteristics. In addition they tested three standard therapies for neuropathic pain from three drug classes: oxycodone, gabapentin and amitriptyline (narcotics, gabapentanoid anticonvulsants, and selective serotonin reuptake inhibitors, respectively). They reported near-identical results with respect to analgesic effect in different neuropathies (hypersensitivity to heat and pressure). Interestingly not all endpoints within a given model were equally responsive to a specific drug intervention. Hypersensitivity to heat and pressure were responsive to oxycodone, gabapentin, and amitriptyline; but cold and mechanical allodynia were harder to treat. They also found that amitriptyline was virtually without effect upon CCI- and SNLinduced mechanical allodynia [32]. This emphasizes that the origin of the

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neuropathy must be considered when designing an appropriate therapy. Clearly the fact that near-identical results in a number of different neuropathies (hypersensitivity to heat and pressure) is of little or no import if the desired symptomatic relief cannot be achieved. Infraorbital nerve ligation in the murine model was used in another study that sought to differentiate the efficacies of the selective serotonin reuptake inhibitor, clomipramine, and the mixed narcotic selective norepinephrine reuptake inhibitor, tramadol. Following the establishment of neuropathic pain both drugs were used to treat the responses to cooling and chemical irritation from acetone and chemical irritation (formalin, capsaicin); but tramadol was found to be ineffective on capsaicin- induced chemical irritation. This study lends support to the consideration that there are differences in the response to therapy for neuropathic pain based upon the origin of neuropathic pain. Again the need for mechanism specific treatments is made clear [33]. The role of cytokines in PIN was explored in a murine model when Uceyler et al. induced chronic constriction injury of the sciatic nerve and measured cytokine gene expression. The study used interleukin 4 (IL-4) knockout (KO) mice and compared them to wild type mice following CCI. The difference between the two lay in the development of tactile allodynia following the injury event. Mice that lacked IL-4 displayed tactile allodynia. Responses of IL-4 KO mice to heat and cold stimuli and to muscle pressure were the same as in control animals. The group also noted that IL-1β gene expression was increased and that IL-10 gene expression was elevated as well. In addition, CCI-induced gene expression of μ, κ, and δ opioid receptors in the contralateral cortex and thalamus of IL-4 KO mice, which was paralleled by fast onset of morphine analyzed. This was not observed in WT mice. They concluded that lack of IL-4 leads to mechanical sensitivity and the compensatory hyperexpression of analgesic cytokines and opioid receptors after CCI. These changes serve a protective role in IL-4 KO mice from enhanced pain behavior following CCI [34]. This work also suggests possible therapeutic options based upon interleukin manipulation. One notable therapy would be the use of IL-4 viral DNA transduction [35]. The relationship of electrophysiologic events post neural injury and specific symptoms of neuropathic pain was proposed in a study by Djourhi in which the group created total axotomy (spinal nerve axotomy L5- SNA), and a compression injury (modified SNA- addition of loose ligation of L4 with neuroinflammation-­ inducing chronic gut). They identified the following electrophysiologic occurrences in L4/L5 DRG neurons and ipsilateral L4 receptive field neurons: increased percentages of C, Aδ, and Aβ nociceptors and cutaneous Aα/β low threshold mechanoreceptors with ongoing spontaneous firing; spontaneous firing in C-nociceptors originating in the periphery (faster in modified SNA than SNA); decreased electrical thresholds in A- nociceptive and Aα/β LTM after SNA (but not C nociceptors); increased slope of somatic action potential rise times in C- and A-nociceptors [36]. Their proposed contribution of the changes to specific neuropathic symptoms is summarized in Table 1. The question of whether opioids can directly inhibit primary afferent neuron transmission of mechanical stimuli in neuropathy was raised in a 2012 study by

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Table 1  Summary of proposed contribution of the electrophysiologic changes to specific neuropathic symptoms [36] Electrophysiologic characteristic Spontaneous firing in nociceptors Spontaneous firing of Aα/β Lowered A-nociceptor electrical thresholds

Symptomatology/clinical sign Ongoing/spontaneous pain Dysesthesias/paresthesias A-nociceptor sensitization and greater evoked pain

Schmidt et al. If opioids can inhibit this transmission, there could be an important role of some opioid agonists in managing the development and sustenance of compressive neuropathy. In this study the μ-opioid receptor agonist [D-ala2, N-Me-­ Phe4, Gly5]-ol-enkephalin (DAMGO) was found to significantly elevate the mechanical threshold of nociceptive Aδ and C fibers. DAMGO also diminished mechanically evoked discharges of C nociceptors in injured nerves. To support the experimental argument of DAMGO efficacy in this work antagonism of DAMGO and washout of the agonist itself reversed the mechanical threshold elevation of the Aδ and C fibers and reversed the diminution of the mechanically evoked discharges of C fibers in injured neurons. They concluded that the opiate effect of DAMGO (no other opiates were examined in this work) did not alter the responses of sensory fibers in uninjured nerves, but that neuronal injury renders nociceptors sensitive to opioids [37]. This finding and its subsequent application may present a dilemma given the current opiate crisis and any recommendation that an opiate should be a first or second line treatment for PIN. Interestingly, complete transection causes a different pattern of neuronal excitability in the trigeminal sensory nucleus (TSN) than chronic constriction injury. Abe et al. examined c-Fos induction in a murine model following chronic transection using electrical stimulation of the trigeminal ganglion at C-fiber activating conditions. They noticed that constricted but not transected trigeminal nerve models resulted in increased immunoreactivity to c-Fos in the superficial layer (I and II) of the Vth cranial nerve nucleus caudalis in its full extent but less so in the principal oral and interpolar nuclei. Complete transection of the inferior alveolar nerve, infraorbital and masseteric nerves resulted in increased c-Fos induction as well in the rostral TSN and magnocellular zone of the Vc, but decreased c-Fos levels in the central terminal fields of the transected nerve and increased c-Fos outside those fields. The authors stated based upon this finding that trigeminal nerve transection increases the irritability of TSN that receive inputs from injured mechanoreceptors and uninjured nociceptors but decreases it from injured nociceptors [38]. The interplay of glycinergic inhibitory circuits in the prevention of low threshold mechanoreceptors (Aβ fibers) cross-firing with nociceptors in the dorsal horn and the disruption of this relationship by constrictive nerve injury was discussed by Lu et  al. Blocking glycinergic synaptic transmission was shown to induce marked mechanical allodynia which pointed directly to the existence of this relationship, at least in the murine model [39]. It is analogous to glia-mediated glycine transport inhibition that is shown to decrease neuropathic pain behavior in the murine model and is also thought at least in part, to be responsible for the prolonged relief from CRPS caused by the local anesthetic lidocaine [40].

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Sensory fibers in the skin play a role in the maintenance of mechanical hyperalgesia following SNI. This hyperalgesia began as early as 24 hours following SNI and lasted for at least 6  months. Teased fiber recordings on spared sural nerve revealed that Aδ mechanoreceptors and C fibers in a murine model fired significantly more action potentials in response to suprathreshold mechanical stimulation than did controls or sham operated animals. They concluded that enhanced suprathreshold firing in Aδ mechanoreceptors and C fibers may play a role in marked, persistent mechanical hypersensitivity. Interestingly this study showed no increase in spontaneous activity in the SNI model [41]. A paradoxical relationship between ultra-low dose (ULD) μ opioid receptor agonism which is thought to create opioid induced hyperalgesia and tolerance as well as varying degrees of effective analgesia following nerve injury exists in a murine model [42]. Wala et al. examined the acute administration of fentanyl in non-injured rats. They also administered chronic fentanyl to rats both immediately following chronic constriction injury on days 1–28 following the establishment of neuropathy on days 7–14 in nerve-injured rats. The group found the creation of OIH in the non-­ injured rats as was expected and an inverse relationship of dose to intensity of OIH (measured via tail-flick and paw pressure test).The OIH was reversed by ketamine. Of note was the finding that rats exposed to ULD fentanyl from day 1–28 following chronic constriction injury did not develop neuropathy. A parallel trial using the κ-opioid agonist (U50488H) under the same conditions as fentanyl (μ-opioid agonist) did not result in prevention of neuropathy. The group concluded that ULD μ-opioid but not κ-opioid blocked the initiation but not the maintenance of neuropathic pain after CCI in rats. The apparent questions following this work and its findings are first: does the same relationship exist in a human model; second: how does the clinician identify the patient at increased risk for post-procedure neuropathy development; and third: should ULD fentanyl be used empirically in all patients at risk for compressive nerve injuries? Receptive field properties were analyzed in the pressure-injured murine model via intracellular recordings of L4 dorsal root ganglia of anesthetized rats 1 week following L5 partial spinal nerve ligation by Boada et al. Their work revealed that in addition to the occurrence of demonstrable neuropathic pain behavior occurred within 1  week. In addition, L5 injury resulted in sensitization of high threshold mechanoreceptor, A-fiber cells at the L4 level. These fibers demonstrated a seven-­ fold increase in receptive field area, a doubling of maximum instantaneous frequency in response to peripheral stimuli, and reductions in both after-hyperpolarization amplitude and duration. Uninjured sensory nerves which transitioned to innervating areas of hypersensitivity after injury of adjacent nerves generated massive altered input. The group also noted a reduced tactile and an increased nociceptive afferent response [43]. In an excellent conceptual work in 2016, focus was placed upon the molecular mechanisms which govern sensory neuron subtype excitability. Venteo et al. demonstrated that the Na, K-ATPase modulator Fxyd2 is specifically required for setting the mechanosensitivity of Aδ-fiber low-threshold mechanoreceptors and sub-­populations of C fiber nociceptors. Loss of Fxyd2 function either genetically (Fxyd2 -/-), or

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acutely (specific molecular inhibition) alleviates mechanical hypersensitivity caused by peripheral nerve lesions. This group then identified the equivalent of Fxyd2 in the human DRG which sets the stage for exploration of therapeutic targeting of this molecule in the treatment of neuropathic pain [44]. The role of macrophages in compressed nerve injury was described in the setting of accidental mandibular nerve injury in a study that utilized inferior alveolar nerve transection in a murine model. Following neural injury implementation, mechanical head-withdrawal threshold (MHWT) was measured continuously for 15 days. The macrophage activity marker, ionized calcium-binding adapter molecule1 (Iba1), was examined on day 3 following the neural injury and the MHWT on the ipsilateral side was measured following stimulation of the whisker pad skin. The macrophage depletion agent, liposomal clodronate Clophosome-A (LCCA) was administered into the trigeminal ganglion during this time period. The group measured TNFα and TNFR immunoreactive cells in the trigeminal ganglion on day 3. Intra ganglion administration of LCCA reduced the number of Iba1-IR cells and reversed the injury induced decrease in MHWT. The group also administered the TNFα inhibitor etanercept and found that MHWT reduction was recovered as well in this setting. They concluded that TNFα signaling cascades produced by macrophages infiltrating into the TG contributes to mechanical allodynia following compression injury [45]. Further work examining mediators of neuropathic pain at the subcellular level focused upon the role of peroxisome proliferator-activated receptor- gamma isoform (PPARγ). When induced, PPARγ is known to block the expression of proinflammatory factors such as COX2, IL-1, and TNF [46]. PPARγ was shown to increase 3 weeks after TIC nerve injury and also to attenuate trigeminal hypersensitivity in a murine TIC nerve injury model. The authors of this study postulated that utilizing the FDA approved diabetic treatment drug the PPARγ receptor agonist, pioglitazone (PIO) may be valuable in the treatment of orofacial neuropathic pain [47]. We postulate further that a possible approach may be viral transduction of the PPARγ DNA sequence to the DRG to regulate the neural response to the inflammatory changes of compressive neural injury. A comparison between initiators of allodynia was constructed in order to explore differences in neuropathic behavior in murine models of neuropathic pain. The models used approximated humoral injury and compressive nerve injury. The applied neural insults were inflammatory “soup” (prostaglandins, serotonin, bradykinin, histamine, substance P, and leukotrienes- IS) applied to the meninges and CCI of the IoN; humoral injury and compressive injury respectively. Different behaviors were elicited depending upon the stimulus. Mechanical withdrawal threshold of the bilateral vibrissal pad and the right-sided (ipsilateral) periorbital area were determined in both the IS and IoN-CCI groups. In only the IS subset was there lowering of mechanical withdrawal threshold in bilateral periorbital regions. Thus the inflammatory soup subset demonstrated a wider range of allodynia than did the IoN-CCI group. The variability in bilateral and unilateral responses suggests first that there may be humoral “spillover” into the circulation that is responsible for the bilateral threshold depression of the mechanical withdrawal threshold. This was absent in the CCI model and suggests that humoral involvement, at least as far as a significant spread in the circulation is concerned, is absent in the compressive injury

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model. The study did reveal bilateral vibrissal stimulus MHWT depression in the compressive nerve injury model [48]. This suggests that either significant neural crosstalk or crossover occurs in the CNS following constrictive injury, or that the humoral response in this setting is sufficient to access the circulation and that the chemical mediators of the neural injury arrive at the contralateral vibrissal pad at a concentration sufficient to elicit MHWT depression. Another study that implicated the spread of neuropathy from the site of a “local” compressive injury again employed partial infraorbital nerve transection. The toll-­ like receptor (TLR4) which binds lipopolysaccharide (LPS) and other products of tissue injury and thus play a role in triggering the neural injury response cascade was examined in this work. The group found that a C3H/HeJ point mutation in the TLR4 gene (Tr4) or a spontaneous deletion (C57BL/105cNJ) and the resultant TLR4 deficient mice failed to develop allodynia in the hind paw. The next step in the experimental argument, pharmacologic antagonism of TLR4 with lipopolysaccharide from the Rhodobacter sphaeroides bacterium (LPS-R5) which is a potent antagonist of LPS also resulted in the elimination of hindpaw allodynia. It is worthy of note that in WT animals following partial IoN transection TNFα expression was upregulated in both the medulla and the lumbar cord; the expression of MyD88, a downstream molecule of TLR4 however was increased only in the lumbar cord. In addition, hind paw hypersensitivity following partial sciatic nerve ligation was attenuated by TLR4 deletion. The hypersensitivity did not spread to the vibrissal pad (trigeminal ganglion distribution); was accompanied by upregulation of MyD88 in the lumbar cord (which implied activity of TLr4); and did not result in upregulation of MyD88 in the medulla. The group concluded that while TLR4 participates in the spread of orofacial pain-related allodynia to distant body sites, trigeminal neuropathic pain and its hyperalgesia component does not [49]. The voltage-gated potassium (Kv) channels have been shown to be important regulators of nociceptive excitability. The subfamily S member 1 variant is a protein encoded by the KCNS1 gene, and it is associated with neuronal hyperexcitability (and therefore possible excitotoxicity) and mechanical sensitivity in at least one murine model and the increased risk of developing chronic pain in humans. Tsantoulas et  al. demonstrated a protective function of Kcns1 when they first showed that Kcns1 is predominantly expressed in Aδ fiber nociceptors and Aβ LTM; detected Kcns1 in laminae III to V of the dorsal horn (the terminus of the majority of A fibers); and detected the presence of Kcns1 in large motoneurons of thee ventral horn. They used gene deletion techniques to remove/inactivate Kcns1form all sensory neurons and found that Kcns1 KO mice showed exaggerated mechanical pain responses and hypersensitivity to both noxious and innocuous cold which they determined was consistent with increased A fiber activity. They also concluded that Kcns1 function in the periphery likely ameliorates mechanical and cold pain in chronic states. Again we propose that viral transduction of Kcns1 mRNA may be of value in creating desired degrees of Kcns1 upregulation in mechanical allodynia and possibly other neuropathic conditions [50]. Entrapment syndromes were again addressed when an IoN-CCI model was employed and asymmetric facial grooming was accessed. They determined that “improved” Ion –CCI surgical procedures makes the murine model more accessible

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Table 2  Pressure-induced neuropathy Low threshold mechanoreceptor Action potential genesis AP duration AP amplitude Aβ Fiber excitability Abnormal axonal sprouting of myelinated axons in laminae IV/V

Cancer-induced pain ↓ ↑ ↓ ↑ ↑

Neuropathic pain ↓ ↑ ↓ ↑ ↑

[51]. In our literature search we were unable to find any studies (including the one described here) that compared IoN-CCI techniques in an unbiased fashion [51]. The calcium sensor protein regulates release of glutamate by acting in concert with N-terminal EF hand Ca++ binding protein (NECAB2). NECAB2 has been shown to be present Aβ and Aδ fibers and in protein kinase Cγ-containing excitatory spinal interneurons. NECAB2 was downregulated by peripheral nerve injury. This may be considered a protective response against pain in an injury setting, i.e. activation of a molecular pathway (NECAB2 downregulation) that contributes to the limitation of an excitatory neurotransmitter, glutamate. In a 2018 study Zhang et  al. addressed the role of NECAB2  in pain circuits at the DRG.  They showed that NECAB2 loss of function (as in NECB2 -/- mice) facilitates behavioral recovery following peripheral nerve injury and the subsequent development of neuropathic pain. This is accomplished in part, they assert, via the decrease in production and release of brain-derived neurotrophic factor (BDNF), and proinflammatory cytokines. The targeting of NECB2 expression and its presynaptic receptor site are postulated as potential sites for therapeutic intervention in the clinical setting [52]. PIN pain studies were conducted by Zhu et al. in an attempt to mimic both nociceptive and neuropathic components of cancer -induced pain in a murine model. They used a polyethylene cuff implanted around the sciatic nerve to initiate the neural injury, and in two parallel study components MATLyLu rat prostate cancer cells or mammary rat metastasis tumor-1 rat breast cancer cells were implanted into the distal femoral epiphysis and electrophysiologic and morphologic changes were assessed and compared in LTM (Table 2) [53]. As a point of interest, it is worth noting that cancer induced pain apart from chemotherapy induced peripheral neuropathy shares features with neuropathic pain and according to the model in this study, PIN pain. The logical question at this juncture is whether proposed, novel interactions for managing PIN holds any promise in the treatment of cancer induced pain and in particular cancer induced bone pain.

Human/Clinical Studies Mechanosensation remains the most difficult sensory modality to mechanistically describe. This is in spite of the fact that compression neuropathies are relatively common and carry significant functional disability. The transition of Aβ fibers

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Metapyrone

Cortisol

241 NMDA Receptor Activation

Fig. 4  Schematic of the potential beneficial effect of decreased cortisol upon neuropathic pain. Here, this decrement is triggered by the addition of metapyrone

which normally transmit only non-noxious information into carriers of noxious information was examined by Baron et al. in 2010. This group used microneuropgraphic single fiber recordings to reveal abnormal ectopic activity of myelinated mechanosensitive fibers in traumatic nerve lesions, entrapment neuropathies, and radiculopathies. They found that ectopic nerve activity correlated in intensity and time course to the reported paresthesias and concluded that this is likely due to pathologic activity in A-fibers. Normally impulses in Aβ remain isolated from the nociceptive system, however when peripheral nerve damage occurs these mechanoreceptor manage to gain access to the nociceptive system and a pain perception results. It is also believed that in these patients, sensitive mechanoreceptors with large myelinated axons exist that normally encode non-painful tactile stimuli. This phenomenon was confirmed by reaction time measurements showing conduction velocities that were consistent with large myelinated axons; pain evoked by stimulus intensities that only produce tactile sensations in healthy skin; the use of differential nerve blocs to demonstrate the loss of pain sensations when tactile sensations are lost but other modalities remain unaffected. The group concluded that paroxysmal pain is related to Aβ fiber demyelination [54]. Alterations in the hypothalamic pituitary axis were examined as contributors to the development and maintenance of PIN. In this study 20 healthy volunteers were entered in a randomized placebo-controlled crossover trial. Metapyrone-induced hypercortisolism was performed and basal mechanical pain sensitivity, perceptual wind-up; and temporal summation of pain elicited by inter-digital web pinching (IWP) were all assessed in this setting. Hypercortisolism was found to decrease pain detection thresholds and to augment temporal summation of IWP-induced pain. In addition this was consistent with an inhibitory effect upon NMDA receptor activation by glucocorticoid receptor antagonists. In light of this finding, the question of cortisol having a beneficial effect upon neuropathic pain may need to be revisited [55] (Fig. 4).

Migraine Headache A 2009 study logged into www.clinicaltrials.gov sought to examine the role of the NOS inhibitor and 5HT agonist NXN-188 in the treatment of acute migraine attacks with aura. While the study was not completed it brings light upon the previously defined role of nNOS and its relation to development of hyperalgesia [56]. In brief, the induction of nNOS induces an increase in cytoplasmic Zn++ which then acts as a chaperone of protein kinase C γ to the plasma membrane where the kinase can then phosphorylate the C terminus of glutatergic receptors and alter receptor removal from the membrane [57].

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Migraine headache which is thought to be at least in part secondary to entrapment of branches of the trigeminal ganglion is also now thought to be generated by the release of peptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) by afferent fibers of the superficial temporal artery. The authors tested the hypothesis that topical capsaicin, a potent agonist of the TRPV1 channel can cause improvement in migraine symptoms. The group found a greater than 50% reduction in pain in the absence of an attack (temporal arteritis only) and a greater than 50% reduction in pain in patients who were suffering mild-to-moderate intensity headaches. They concluded that more active capsaicinoids might be tried in future studies. Of even greater interest to us is the fact that this reinforces the mechanistic link between transient receptor potential types and PIN and introduces a new consideration of where pharmacologic interventions may be made in order to interrupt this disease process [58].

Carpal Tunnel Syndrome The role of “pressure” in carpal tunnel syndrome (CTS) qualifies this as a PIN and is iterated in an article by Thurston in 2013. He re-visits the decrement in capillary and vaso nervorum blood to subthreshold levels and the resultant loss of median nerve function then viability. He states that CTS can result from direct trauma but there are risk factors for CTS that he discusses and then ranks them [59]. A pressure related sequel to successful treatment of CTS is deep-seated wrist pain which is worsened by leaning on the heel of the hand can occur after carpal tunnel release (CTR) surgery. In a 2018 study Roh et al. reviewed the experience of one surgeon performing 162 open CTR procedures over a 35-month period. One hundred thirty-one patients (mean age 54 years, 81% female) completed the study and were analyzed. They found that female gender, preoperative pain sensitization measured by pressure pain threshold and self-reported Pain Sensitivity Questionnaire were directly related to pillar pain severity from 3 to 6 months following CTR. This relationship was shown to diminish at 6 months and by 12 months was essentially non-existent [60].

Lumbar Radiculopathy A clinical model of PIN was examined by Blond et al. in a 2015 systematic review of the literature regarding failed back surgery syndrome (FBSS). This syndrome, which occurs beyond the initial injurious lesion and as a result of a surgical intervention of the spine, is thought to be the result of direct injury to the spinal cord and/or nerve root or by the imprinting of a morphological change of the neural tissue [61]. This work reviewed the clinical literature from 1930 to 2013. It identified and iterated the inflammatory response to nerve injury as the initiation of the aversive sensation provoked by the activation of LTM as the primary cause of FBSS.

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Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) A genetic model in humans for compressive nerve injury exists in the hereditary neuropathy with liability to pressure palsy syndrome (HNPP). This disorder is caused by a loss of function of the peripheral myelin protein 22 gene. (PMP22). In a case report of this previously untreatable disease a female patient with HNPP who presented with symptoms of a painful neuropathy received trial doses of intravenous immunoglobulin G (IVIg) in a double blind, placebo-controlled n-of-one trial. The patient received four trial infusions (3 placebos, and 1 IVIg). She requested three rescue infusions all after the placebo infusions and none after the IVIg infusion. In addition muscle weakness that was associated with the neuropathic pain was also reduced by the infusion of IVIg but not the placebo infusion. The group came to the conclusion that IV Ig infusion warranted more clinical investigation in the settings of HNPP and its variants [62].

Inguinal Entrapment Syndrome In another clinical setting of compressive nerve injury, severe, persistent inguinal postherniorrhaphy pain (PIPP) was studied. In this randomized double-blind placebo controlled crossover trial 14 PIPP patients and six healthy volunteers received 0.25% bupivacaine or normal saline ultrasound-guided fascial pain block at the symptomatic tender point. Statistically significant pain reduction was noted with the local anesthetic injection as well as significant increases in cool detection, increases in pressure pain thresholds; and decreases in supra threshold heat pain perception. The authors concluded that peripheral afferent input from the tender point area is important for maintenance of spontaneous and evoked pain in PIPP [63]. Whether this TP is the actual lesion in the peripheral nervous system remains unknown. Chronic postoperative inguinal pain (CPIP) was re-visited in a registered clinical trial in 2018. The group sought to determine the actual rates of CPIP but found that the incidence reported in different studies range from 9.7% to 51.6%. The causes of CPIP remain unclear as well with nerve entrapment, neural lesioning, mesh type, and mesh fixation material all being implicated in the syndrome development. In addition, the study found that that by IASP definitions the symptoms of CPIP allow it to be divided into neuropathic and non-neuropathic categories. The group asserts that pressure and the use of foreign materials such as suture can cause intense inflammation and generate nociceptive pain. They conclude that a low-pressure (and hence a lower irritation-injury) technique such as glue attached meshes should be used preferentially [64].

Miscellaneous Human Models of PIN Residual sensitization of the pain system following a recent painful injury was studied by Palsson et al. in 2018 when they compared patients who had recently suffered

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an ankle injury with healthy controls. The group measured pain intensity, pain referral patterns, and pressure pain thresholds. These were measured in close proximity to but not at the injury site, and at a site that was remote to the injury. The group found that referred pain reports came more frequently from remote sites in the pain-­ recovered group than in the control group, and that there were no group differences found in pressure pain threshold, pain detection threshold, pain tolerance and temporal summation of pain. In the final analysis it was determined that a larger prospective study was needed to clarify the time frame and functional relevance of these changes in recovering pain conditions [65].

Treatments and Summary In summarizing the therapeutic prospects found in this search we consider some the following considerations. Given the controversy surrounding the previously widely accepted global use of narcotics to treat neuropathic pain of all origins and pain in general we focus upon the study by Wala et al. in 2013. Here they demonstrated that some neural injuries rendered nociceptors susceptible to opiates. It follows that rather than omitting the use of opiates altogether, the timing of opiate use may be the critical step. That is, opiates may best be implemented during or immediately after the injury event. Regarding the ability to manage neuropathic pain following its establishment, the work of Venteo et al. in 2016 examined the modulation of the firing rate of Aδ and C fibers using the Na, K ATPase modulator Fxyd2 shows exciting promise however the extrapolation from the non-human to the human model while maintaining highly specific neuronal activity poses one of the largest challenges to the use of this molecule to treat PIN. The PPARγ agonist pioglitazone may be of value in limiting PIN in the murine model, its accepted, extant clinical use as an anti-hyperglycemic, however suggests that trials are needed for its use in diabetic peripheral neuropathic pain and perhaps more appropriately in the setting in which the diabetic patient is at risk for a double crush injury event. Selective macrophage depletion with LCAA may be of some use however it may be difficult to assess the organismal ecologic effect of a decrease in macrophage population. We recognize several constructs in which the application of viral DNA transduction [35] may prove of value in the treatment of neuropathic pain. While the concept itself is not new the genetic data that comes to light as potential informational cargo appears to be ever evolving. For instance, native molecules found to be protective against PIN (and indeed any variant of neuropathic pain) may be transduced in an upregulated form then switched off via programmed chemical degradation when they are no longer needed in their state of increased activity. The molecules that come to mind most readily are Fxyd2 [44], KCNK [17–19], KCNS1 [50], and IL-4 [34]. Each of these molecules must first be subjected to rigorous bench study and the refinement of toxicity profiles prior to meaningful use in the described fashion in human and non –human models, but examination of these and other promising

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agents may hold the solution to the management of this most burdensome of neuropathic pain syndromes.

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Infectious Neuropathies Hai Tran, Daryl I. Smith, and Eric Chen

Introduction Numerous infectious agents are probable causes of neuropathies. Probable because the elucidations of mechanisms that establish the causal relationships between these entities to the associated neuropathies are not entirely elucidated, sparse, or unknown. Infectious neuropathies may occur in either the early or chronic phase of the infection; or they may occur much later as part of a reactivation after an extended latency. Prior to the advent of vaccines, specific treatments, and advanced diagnostic capabilities, neuropathies associated with infectious diseases were unfamiliar, undiagnosed  and prevalent.  Early diagnosis and treatment can often prevent the evolution of neuropathies or mitigate the development of symptoms, morbidities, and mortalities associated with such neuropathies. The overall prevalence of neuropathies associated with infectious elements decreases due to better preventive health measures, especially vaccines, and treatments/cures of the underlying infectious causes. Better preventive health measures have led to a decrease in the prevalence  of infectious disease-related neuropathies. The  prevalence of neuropathies associated with specific chronic infectious diseases for which there is no vaccine or definitive cure is higher because of longer life expectancies as a result of improved containment strategies and symptom alleviation. This trend will likely H. Tran URMC Strong Memorial Hospital, Department of Anesthesiology and Perioperative Medicine, Rochester, NY, USA D. I. Smith (*) University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA e-mail: [email protected] E. Chen Department of Anesthesiology & Perioperative Medicine, University of Rochester Medical Center, Rochester, NY, USA © Springer Nature Switzerland AG 2022 D. I. Smith, H. Tran (eds.), Pathogenesis of Neuropathic Pain, https://doi.org/10.1007/978-3-030-91455-4_13

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Table 1  Common infectious causes of neuropathies Prions Spontaneous Genetic Acquired

Viruses SARS-CoV-2 HIV1/2 Hepatitis A, B, C, and E Human herpes viruses: HSV1, HSV2, varicella zoster virus, and cytomegalovirus Flaviviruses: Zika, and West Nile Lyssavirus: Rabies virus

Bacteria and Toxins Parasites Bacteria: Leprosy, Lyme, Chagas’ disease Toxins: Diphtheria, botulism, tetanus, and tick paralysis

SARS-CoV-2 severe acute respiratory syndrome – coronavirus - 2, HIV human immunodeficiency viruses, HSV herpes simplex virus

continue until preventive measures and specific treatments are developed which curtail the incidence and prevalence of the pathologies causing these neuropathies. The literature suggests that any agent, infectious or noninfectious, can contribute to the development of neuropathies directly, indirectly, or by an autoimmune driven etiology, or as a coalition, against a specific antigen or non-antigen via a multiplicity possibilities and combination of mechanisms. The intermediaries might include direct toxicity, vasculitis mediated ischemia, cellular and/or humoral immune response, immune complex deposition, and cellular infiltration, to name a few. However, the final pathway in neuropathy’s evolution is the inflammatory response and the involvement of the cytokines, suggesting that this terminal process is critical. Bodily functions are intricated yet distilled to an elegant operation. Ideally, potential therapeutics should target the many pathways. However, treatments can still be developed directing at the final pathway, notwithstanding the understanding of these complex processes and their interwoven dynamics. Following neuronal injuries, nerve growth factor initiates the repair/apoptosis and regeneration process. The role of nerve growth factor as part of the systemic immune response is also paramount in establishing neuropathies. The complex interdependence relationships among signaling pathways responsible for inflammation, repair, apoptosis, regeneration, and growth will determine whether the initial inciting factor will lead to neuropathies and/or recovery. At this juncture, little is understood, and even less is known about tipping the balance in favor of repair, regeneration, and growth of damaged nerves. This chapter summarizes familiar infectious entities that have been associated with peripheral neuropathies. Table 1. lists variables associated with neuropathies, and it is by no means exhaustive for reasons stated previously.

Prion Disease – Related Neuropathies Prion disease, also known as spongiform encephalopathy, was first described in the 1920s by Alfons Jakob after he noticed neurodegenerative cases that were similar to those described by Hans Creutzfeldt. Prion disease is now known to be caused by the conversion of a protein PrPC, which has a primarily α-helix structure, to PrPSc,

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which is primarily a β-pleated sheet structure [1–3]. Since then, prion diseases in humans have been categorized by three forms: spontaneous, genetic, and acquired. Spontaneous forms of prion disease include Creutzfeldt-Jakob disease, variably protease-sensitive prionopathy, and sporadic fetal insomnia. Genetic forms include familial Creutzfeldt-Jakob disease, Gerstmann–Sträussler–Scheinker disease, and familial fatal insomnia (FFI). Lastly, acquired forms include kuru, iatrogenic Creutzfeldt-Jakob disease, and variant Creutzfeldt-Jakob disease [4]. Prion disease can present in several different ways depending on the specific type. For example, Creutzfeldt-Jakob disease is classically associated with progressive dementia with behavioral changes, ataxia, extrapyramidal features, and myoclonus. Fatal familial insomnia presents with severe progressive insomnia and dysautonomia followed by late manifestations of motor and cognitive symptoms [1]. There have been reports of atypical presentations of prion disease including peripheral neuropathy, gastrointestinal symptoms, amyotrophy, and even one report of vulvodynia [4–7]. The pathophysiology of neuropathic pain secondary to prion disease is still unknown. Looking into peripheral neuropathy, Baiardi et  al. demonstrated using Western blotting that the peripheral nerves of patients with peripheral neuropathy contained PrPSc, though in a lower concentration that those found in the frontal cortex of a “typical” person with prion disease. Additionally, these authors observed that in sural nerve biopsies of patients with peripheral neuropathy, there were prominent signs of axonal damage and demyelination. They noted that in peripheral nerves in certain phenotypes of sporadic Creutzfeldt-Jakob disease, specifically sCJDMV2K (kuru-plaque type) and sCJDVV2 (ataxic type), were associated to have PrPSc deposition. Similarly, they noted a lower prevalence of peripheral nerve involvement in other strains suggesting that peripheral nervous system involvement may be strain dependent [8]. In terms of the physiologic function of PrPC, it is thought that it may be involved in neuroplasticity, neurotransmission, copper homeostasis, and myelin maintenance [4]. In 1992, Neufeld et  al. reported two patients of Jewish-Libyan descent with Creutzfeldt-Jakob disease who were found to have demyelinating disease [9]. In a mouse study to demonstrate a new prion disease model, Nuvolone et al. suggested that PrPC may have a role in peripheral myelin maintenance. In their mouse model of prion disease, they observed that these mice would develop chronic demyelinating peripheral neuropathy as they aged [10]. While looking into PrPC’s role in depression, Gadotti et al. reported that PrPC may have a role in inhibiting N-Methyl-D-aspartate receptor (NMDA) receptor activity. In this study, they observed a reversal of depressive symptoms when PrPC knockout mice were given an NMDA antagonist, MK-801 during a tail suspension test designed to induce depressive symptoms [11]. In a separate study, Gadotti et al. looked at PrPC and its effects on the NMDA receptor in the context of pain, given NMDA’s important role in pain transmission in the dorsal horn of the spinal cord. In this study, PrPC knockout mice were exposed to inflammatory and neuropathic pain in the form of formalin-induced inflammation or glutamate injection into the paw respectively. Both forms of pain were sensitive to MK-801, which decreased the

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mice’s pain response, which was measured by paw withdrawal threshold. Additionally, they found that sciatic nerve ligation resulted in MK-801 sensitive neuropathic pain in wild-type mice but did not further increase basal pain behavior in the PrPC knockout mice suggesting that PrPC may have a role in nociception at the central and/or spinal cord level [12].

Viruses Covid-19 Related Neuropathies As of this writing the coronavirus pandemic caused specifically by the SARS-CoV-2 variant of the coronavirus family has claimed close to a million lives worldwide and over two hundred thousand lives in the United States alone [13]. The human coronaviruses have been recognized as known pathogens of the upper respiratory tract being mainly associated with mild pathologies such as the common cold. Severe forms of the related disease manifest as involvement of the lower respiratory tract. This includes exacerbations of asthma, respiratory distress syndrome and severe acute respiratory syndrome (SARS). The occurrence of the severe form correlates with the existence of compromised immune surveillance. These vulnerable populations include (newborns, infants, the elderly and immune-suppressed individuals [14]). The usual presentation of the disease includes fever (43.8%); cough, and myalgias with gastrointestinal symptoms occurring less often. A significant challenge to diagnosis lies in the fact that some individuals may have no symptoms at all and first, unknowingly spread the disease or, second, rapidly progress to severe or life threatening disease manifestation in a matter of hours [15]. Most recently the press has described reported anomalies such as the existence of normal-appearing ventilation in the face of severe hypoxemia or “happy hypoxemic” syndrome. Several of these patients have, by some anecdotal reports, done well in spite of receiving conservative, i.e., non-mechanical ventilator, respiratory support [16, 17]. Other organ systems may be affected by SARS-CoV-2 these include embolic events throughout the cardiopulmonary vascular tree, myocarditis, myocardial infarction and dysrhythmias; seizures, anosmia, hypogeusia, and cerebrovascular accidents; and myalgias and arthralgias of varying intensities [15, 16, 18, 19]. Approximately 35  years ago it was also recognized that human corona virus (HCoV) can cause neurodegeneration with demyelination. This was due in part to over activation of the immune system with possible development of autoimmunity in the CNS of susceptible individuals. Several viruses have previously been characterized as neurotropic. These include the human immunodeficiency virus, measles virus, and the herpes virus. Currently, based upon more recent clinical and laboratory observations, respiratory viruses are now being classified as potent neurotoxic pathogens as well. These include human respiratory syncytial virus, the influenza virus, the human metapneumovirus and the corona virus (CoV). They are not only the leading causes of acute respiratory

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infections each year for children under the age of 5 and in the elderly but have now been described in several reports as having associations with neurological diseases. The symptoms of the syndromes to date include febrile or afebrile seizures, status epilepticus, encephalopathies, and encephalitis [20]. The spread of virus from the respiratory to peripheral nerves and thus to the CNS has implicated the hijacking of motor proteins such as dynein and kinesins, in addition to hematogenous spread in which the virus is delivered directly to the blood brain barrier via normal blood flow and may enter via a number of different mechanisms [21, 22]. In addition, certain variant infections can mimic non-autoimmune neurologic syndromes as well, with MERS-CoV as a prime example in its causing a Guillain-Barre- like neuropathic syndrome [23, 24]. It was thus postulated that HCoV could be associated with any number of human neurological diseases for which the etiology remains unknown and poorly understood [14, 25]. As the name implies, the viral structure has a “crown-like” appearance created by the spikes on the viral surface. Four main subgroups of coronaviruses exist. These are named alpha, beta, gamma, and delta; and seven coronaviruses currently exist that have the ability to infect humans. Coronaviruses belong to the family Coronaviridae and are classified by genus into four groups: alphacoronaviruses, betacoronaviruses, gammacoronaviruses, and deltacoronaviruses. These genera display varying infective capabilities that are summarized in the table below (Table 2). Generally stated alpha- and betacoronaviruses infect avian species, and deltacoronaviruses infect both mammalian and avian species. The coronaviruses are large enveloped, positive-stranded RNA viruses and claim the largest genome among all RNA viruses [26]. The virus consists of at least three structural proteins which include two proteins that are involved in viral assembly; the membrane protein and the envelope protein; a third, spike protein is critical to viral entry into host cells via receptor recognition mechanisms. Both the alpha coronavirus HCoV-NL63 and the betacoronaviruses SARS-CoV bind to the zinc peptidase angiotensin SARS-CoV to the zinc peptidase angiotensin converting enzyme 2 (ACE 2) [26]. ACE 2 binding does not interfere with enzyme function, nor does the enzyme function impair viral function. HCoV-NL63 and other alphacoronaviruses also recognize different receptors. This Table 2  Summary of coronavirus genera and representative species-specific involvement Genera Example NL63, TGEV, PRCV α BCoV, HKU4, MHV, OC43, SARS-CoV, β MERS-CoV, PHEV IBV γ PdCV δ

Species infected Mammalian Mammalian

Miscellaneous SARS-CoV-2 (COVID-19);

Avian Mammalian and avian

NL63 human coronavirus NL63, TGEV porcine transmissible gastroenteritis coronavirus, PRCV porcine respiratory coronavirus, HKU4 bat coronavirus, MHV mouse hepatitis coronavirus, BCoV bovine coronavirus, OC43 human coronavirus, SARS-CoV severe acute respiratory syndrome coronavirus, MERS-CoV Middle East respiratory syndrome, PHEV porcine hemagglutinating encephalomyelitis, IBV infectious bronchitis coronavirus, PdCV porcine delta coronavirus [26]

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receptor diversity of coronavirus can make viral behavior difficult to predict. The spike protein of the betacoronaviruses and, in particular SARS-CoV, consists of at least three structural proteins which include two proteins that are involved in viral assembly: the membrane protein, the envelope protein; and, third, the spike protein which is critical to viral entry into host cells via receptor recognition mechanisms. Both the alphacoronavirus HCoV-NL63 and the betacoronavirus SARS-CoV bind to the zinc peptidase angiotensin converting enzyme 2 (ACE2) [27, 28]. ACE2 binding does not interfere with enzymatic function nor does the enzyme impair viral function. HCoV-NL63 and other alphacoronaviruses also recognize different receptors. This receptor diversity of coronavirus can make viral behavior difficult to predict. The spike protein of the betacoronavirus and in particular SARS-CoV binds tightly to human ACE2. In fact, two binding “hotspots” have been described as existing on the human ACE2 receptor. These hotspots center upon ACE2 lysine residues, Lys 31 and Lys 353 and are buried in a hydrophobic environment [27–30]. Viral interactions with these hotspots renders the corresponding residues of the virus susceptible to a higher rate of mutations [31]. This genetic instability can create in the virus the ability to bind in other species. Membrane fusion by the coronavirus is dependent upon the hemagglutinin glycoprotein component of the S2 stalk of the spike protein (Fig. 1). The fusion event itself is triggered by proteolysis of the spike initiated when the S1-receptor binding occurs. Processing of the spike protein is critical to its ability to bind to the ACE2 receptor. This occurs following entry of SARS-CoV into host cells via endocytosis where lysosomal proteases take their action. Inhibitors of endosomal acidifaicaytion or lysosomal cysteine proteases block SARS-CoV entry. It is also possible for spike proteins to be cleaved by exogenous proteases when SARS-CoV is expressed on cell surfaces. Endogenous, extracellular proteases may also execute at least two of the requisite protease cleavages [26].

Fig. 1  Corona virus spread to the CNS. This may occur via the trigeminal nerve to the trigeminal ganglion (large, dark gray nucleated structure), with subsequent spread to the CNS (light gray fibers), promoting an inflammatory state. This includes the induced secretion of several pro-inflammatory cytokines such as IL-1, IL-6, IL-8 and granulocyte colony stimulating factor

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S-Protein (Spike) The coronavirus spike is a member of Class I viral membrane fusion proteins. It is similar to the fusion protein associated with the influenza hemagglutinin (HA) but it is larger and more complex [32–34]. it is encoded by the coronavirus and synthesized by the infected cell. This includes incorporation into, first, the host cell membrane and then into the budding virus. Some fusion proteins fuse with the cell surface membrane at neutral pH, while others are endocytosed and fuse with the endosomal membrane when the pH is acidified. Conformational changes occur in response to binding of the fusion protein to the host cell or exposure to low pH. These changes expose the fusion peptide and allow juxtaposition of the viral and host cell membranes [33]. Fusion proteins are typically synthesized as fusion-incompetent precursors. These precursors are then proteolytically cleaved into a surface subunit and a transmembrane subunit. The cleavage events are essential determinants of host range. Activation at the S2’ site, a cleavage that takes place in all coronaviruses can occur in several host cellular compartments. Transmembrane protease/ serine protease (TMPRSS) processes SARS-CoV at the cell membrane, while cathepsin L-mediated, protease-mediated triggering of SARS-CoV occurs in the lysosome [35, 36]. A redundancy is built into the S protein which enables multiple proteases to activate fusion and subsequently increase the range of cell types that can be infected by the virus. It has been suggested that specific neurovirulence of SARS-­ CoV-­2 is related to the spike protein. It is here that some of the potential therapeutic interventions may be of value [37]. Coronaviruses can invade the CNS by means of axonal transport. Microtubule-­ dependent processes include fast transport of organelles and slow transport of cytosolic proteins; and may proceed in both an anterograde as well as a retrograde fashion. This microtubule-dependent rapid axonal transport process is one mechanism by which coronavirus particles are carried in an anterograde direction from the peripheral nervous system to the CNS. Interestingly, this transport can be disrupted by drugs that disrupt microtubular integrity such as colchicine, nocodazole and vinblastine sulphate. Later work re-emphasized this and other transport systems as potential targets of therapeutic intervention [22, 38]. There are neurotropic strains of coronavirus that produce experimental neurologic diseases in murine models including chronic inflammatory, immune-mediated demyelination which is a common symptom-generating pathway [39]. Demyelinating immune-mediated neurologic disease, it is believed, may be triggered or exacerbated by a virus-induced mechanism. Genetic manipulation of the membrane spike (S gene) was performed in this study. Here the S gene from a demyelinating virus was replaced with the S gene of a non-demyelinating coronavirus. Those viral particles with the S gene from the non-demyelinating virus caused no demyelination; while the S gene from the demyelinating virus did result in demyelination. This implied that the spike protein is important to demyelination and thus the characteristic neuropathy of at least some viral infections. This same group later sequenced the S-gene and determined that three identical point mutations: 1375M, L6521, and T1087N; likely conferred demyelinating properties to the spike protein [40–42].

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CD8+ T cells, which are responsible for the clearance of infectious viruses, remain in their active form along with viral RNA and may contribute to demyelination pathology. Marten et al., attempted to determine whether persistent demyelination was due to CD8+ T cell activity or from virus-mediated injury. They inoculated mice with two attenuated viral variants which differ in their hypervariable region of the spike protein. One infection was marked by extensive demyelination and paralysis, while the other resulted in no clinical symptoms and little neuropathology. Their results revealed that the paralytic variant was superior in its ability to induce specific CD8+ and that mononuclear cells from both preparations exhibited virus-specific cytolysis which was lost after the infectious virus was cleared. In addition, twice as many virus specific interferon gamma CD8+ T cells were found in the brains of asymptomatic mice compared with mice undergoing demyelination. They concluded that the IFN-gamma, at least in this model was influenced by S protein characteristics; and that IFN –gamma attenuated virus induced demyelination. The specific S- gene sequence identities (2b,4, and 5a) which conferred weak neurotropism upon the MHV-2 variant, suggest that this may be a target for therapeutic genetic manipulation of the critical S protein binding mechanism [41, 43]. Other mutations in the MHV spike protein have been found which confer reduced neurovirulence. In 2001, Matsuyama et al., described three soluble receptor-­resistant (srr) mutants, srr7, srr11 and srr18 derived from the highly neurotropic MHV (JHMV) strain which each have a single amino acid mutation in the spike protein. The srr7 showed reduced neurovirulence, while srr11 and srr18 showed slightly reduced neurovirulence. These differences were determined via measurement of apoptotic cell titers. Interestingly the apoptosis did not appear to be the result of direct viral attack, rather the mutation events in the S protein appeared to have the ability to influence neurovirulence in the murine model [44, 45].

Astrocyte and Microglia Responses to Coronavirus Coronavirus can cause neural damage by simply inducing inflammatory cells to generate proinflammatory cytokines. Interleukin(IL)12, p40, tumor necrosis factor alpha (TNF-α), IL6, Il15 and IL-1β undergo increased expression in infected astrocytes and microglia in a murine model [46]. Immune cells communicate via cytokine secretion [47]. Neurotropic and non-neurotropic strains of coronavirus were used to challenge murine central nervous systems. As predicted, MHV-A59 caused meningoencephalitis followed by chronic demyelination. MHV-A59 also caused both neurons and glial cells to become productively infected. This is characterized by perivascular inflammatory infiltrates which appear 2–3 days after infection. The infiltrates peak on day 5–7 post infection, then decline over 7 days and disappear on day 10 [48]. Viral RNA persists in glia at low levels and the chronic inflammatory demyelinating disease that is similar to human multiple sclerosis develops. In the case of MHV-2 no inflammatory infiltrates are found. This has also been seen in the setting of SARS-CoV in which a cytokine storm occurs that causes respiratory distress and

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multiple organ system failure [49]. Increased neurovirulence is a result of discriminating immune responses of astrocytes and microglia to different phenotypes of viral infections. A potentially massive microglial and macrophage activation is accompanied by the expression of NADPH, with oxidative injury playing a role in the demyelination of multiple sclerosis and multiple sclerosis-like neuropathy [50]. Neurotropism and neurovirulence also depend upon other factors in addition to cytokine secretion. These include viral affinity for cells [26], and viral transport within the CNS [38, 50, 51].

Axonopathic Neuropathy The SARS outbreak in 2002–2003 provided the backdrop for the appearance of a coronavirus-related neuropathic syndrome. Of the nearly 700 probable patients reported in Taiwan, three patients developed axonopathic polyneuropathy 3–4 weeks following the onset of SARS. These patients diagnosed by physical exam and electrophysiologic study, there was spontaneous, symptomatic resolution as the disease resolved. It should be noted that neuropathic pain was not specifically described in this study [52]. The human respiratory coronavirus OC43 strain (HCoV-OC43) was tested specifically as a neuropathogen in a murine model. Using neurons as target cells they noted that degeneration occurred in part due to apoptosis. Infection by HCoV-OC43 was dependent on the route of inoculation, viral dose, the age and strain of mouse. The mice developed acute encephalitis from the neuronal infection. Some neurons underwent apoptosis during the acute phase of the disease which was determined via assay for activated caspase-3 [53]. HCoV-OC423 targets primary hippocampal and cortical cells representative of in vivo brain cells. Coronavirus–induced apoptosis involves host DNA fragmentation and caspase-3 activation. Some non-infected cells in close proximity to infected ones were exhibited apoptotic markers. This suggests that cells (neurons or glia) activated by HCoV-OC43 secreted molecules that induce death signals in non-­ infected cells. An important point here is that infected cultures rapidly released a here is that infected cultures rapidly released a high amount of TNF-α that is thought responsible for apoptosis in neighboring, previously healthy cells [53, 54]. A mutant strain of HCoV-OC43 which harbors 2 point mutations was reported in 2009. The mutations were persistence-associated S glycoprotein mutations designated H183R and Y241H. The mutations lead to caspase-3 activation and nuclear fragmentation. Molecular determinants related to these point mutations result in increased production of viral proteins and infectious particles, enhanced unfolded protein response activation, increased cytotoxicity and cell death [55]. HCoV-OC43 infection is also associated with upregulation of apolipoprotein D (apoD), a lipocalin that appears in the CNS in increasing concentrations following neural injury or certain disease states such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. Interestingly, in the murine model of encephalitis induced by HCoV-OC43, apoD upregulation is associated with the expected glial

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activation, but with a limited innate immune response. That is, there is a limited expression of cytokines and chemokines as well as limited T-Cell infiltration. In addition, there is a measured immune response in the setting of apoD expression. This is in contrast to the potentially lethal chemokine storm found in other virus-­ mediated neuronal infections. This is believed to be the neuroprotective effect which is responsible for the increased survival in the HCoV-OC43 model [18, 56, 57]. Certain variant infections can mimic non-autoimmune neurologic syndromes as well. MERS-CoV is a prime example of this as the symptom complex associated with the infection mimics Guillain-Barre disease. In 1995 Yakamori et al., discussed the critical role of spike protein processing as a determinant of virus neuroinfectivity. They focused upon the neuropathogenicity of the MHV coronavirus in particular and the host enzyme, hemagglutinin esterase (HE). This esterase activation is unique to the betacoronavirus genus. The HCoV S protein is activated by a different method that is not, as of yet, well described. It is important to note that the processing of the coronavirus spike protein imparts critical and often baffling variability to the virus’ capacity to bind to different cell types and in different species. HE cleaves the hemagglutinin glycoprotein moiety of the coronavirus spike protein into the HA1 and HA2 subunits. The HA1 subunit binds to a sugar receptor on the host cell surface and is essential for viral attachment. The HA2 subunit, upon dissociation of HA1 following membrane binding, undergoes an extensive conformational change and transitions to a post-fusion state [26, 51]. Some MHV strains, JHM and A59 in particular, the role of HE is less prominent This is because of instability of the S protein. The JHMSD strain was once deemed more virulent by virtue of the higher number of cells infected, and the larger quantity of antigen expressed when compared to the JHM A59 isolate. The JHMSD strain induced a minimal T-cell response but a strong, potentially harmful neutrophil response. The A59 isolate on the other hand induced a strong T-cell response and concomitant increased expression of IFN gamma that resulted in a relatively neuroprotective effect. In this setting HE activity was not the cause of variability in neurotoxicity [58]. The pattern of viral spread once the CNS has been acquired was described by Takatsuki et  al., in 2010. They examined a highly neurovirulent strain of MHV, JHMV cl-2 and compared it with a less virulent counterpart, soluble-receptor-­ resistant (srr)7. This low virulence strain is dependent upon the carcinoembryonic cell adhesion molecule 1a as a receptor in order to infect cells. The cl-2 variant shows no such receptor dependence to accomplish cellular infection. Significantly, there were no initial differences in viral distribution in the CNS, i.e., between 12 and 24 hours, post-inoculation, in inflammatory cells. At 48 hours, however, cl-2 viral antigens were found in the MHV-receptor devoid grey matter neurons. The srr 7 variants remained in the white matter. Among the inflammatory cells were types that reacted with anti F4/80 and anti CD11b monoclonal antibodies which may be specific for murine microglia and human/murine leukocytes and cell adhesion molecules, respectively [59]. The antigen-positive cells appeared in the subarachnoid space prior to viral antigen spread into the brain parenchyma. They concluded that viral encephalitis began with the infection of infiltrating monocytes that express

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MHV-receptors and that cytotoxic effects of the virus itself upon the monocytes lead to a breakdown of innate immunity and the rapid spread of viruses in the initial phase of the infection [60]. In what may a study critical to the link of viral infection to neuropathic pain associated with coronavirus, Brison et al., studied the excitatory amino acid transport (EAAT) system in the setting of viral infection and activation on the neuroinflammatory mechanisms in the CNS.  They found that viral infection with HCoV-OC43 actively downregulated the expression of the glial glutamate transporter, GLT-1. The transporter is responsible for glutamate homeostasis by way of the removal of this excitatory neurotransmitter rom the tripartite synapse. Failure to remove glutamate from the synapse results in continued stimulation via increase in excitatory post-synaptic potentials currents and, ultimately, excitotoxicity via a pathway of excitation translation coupling. The mediation of this response via a glutamatergic receptor was proven in the study by the addition of the 2-amino-3(5-­ methyl-­ 3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptor antagonist GYKI-52466. While the authors emphasize the connection with paralysis-­associated neuropathology, we have seen an identical affiliation with neuropathic pain processes making it a logical consideration that a similar process may exist in this environment as well [61–63].

Chemokines Chemokines are critical regulators of the cellular immune response to viral infection and in particular to Coronaviridae. Chemokine expression during viral infection promotes the generation and infiltration of immune effector cells needed to shut down viral replication during infection [64]. Chemokine secretion may result also in the development of neuropathology by infiltration of virus specific CD8 + T cells that lead to myeloid and leukocyte entry. Neutralizing chemokines during persistent coronavirus (JHMV) infection reduces immune infiltration and reduces disease severity and demyelination [64–67]. The role of chemokines in the resolution of the demyelination component of virus-related neuropathy was further explored when Carbajal et  al., inhibited the chemokine receptor type 4(CXCR-4) and found that the number of mature oligodendrocyte progenitor cells (OPCs) decreased significantly. It should be noted that mature OPCs contribute to remyelination in response to coronavirus (JHMV)induced demyelination. The authors suggested potential therapeutic benefit from the use of the CXCR-4 inhibitor, AMD3100. Following pulse treatment of infected mice with the inhibitor and subsequent provision of recovery time, they reported that the strategy resulted in increased numbers of mature oligodendrocytes, enhanced remyelination and improved clinical outcome. The authors correctly entertain the potential manipulation of OPCs in order to increase the number of available remyelination-competent cells [68]. Coronavirus demyelination involves not only changes in the chemokine environment but also several genes involved in innate immunity (Table 3). Specifically, there is an increased expression of genes

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Table 3  Innate Immunity-related genes which are upregulated during viral infection Allograft immunity factor 1 NLR family card domain Toll-like receptors G-protein coupled receptors Lysozymes and granzymes Lysosomal associated protein Major histocompatibility complex Fe receptor, IgG, IgE CD antigens Interleukins and receptors Complement component Chemokine (C-X-C) motif ligand Chemokine (C-C) M1 and receptor TNFα and TNF induced protein Guanylate binding protein GTPase very large IFN inducible, GIMAP T cell specific GTPase IFN activated gene Colony stimulating factor Immunity-related GTPase (IRGM)

involved in lipid metabolism that coincides with demyelination. These include genes involved in lipid transport, processing, and catabolism. More importantly microglial activation results in increase cluster of differentiation (CD) cell surface molecules, 11b, 74, 52, and 68; but not 4,8, or19. In addition, there is also robust expression of IFN-γ, IL-12 and mouse keratinocytes (mKC). When activated in the course of a viral infection, microglia and inflammatory mediators contribute to a local CNS microenvironment that regulates viral replication and IFN-γ production. This stimulates maturation of phagolysosomes and subsequent myelin sheath phagocytosis and demyelination [69].

Axonal Transport Axonal transport was also examined in an experiment that showed the retrograde viral transport to the eye via the optic nerve. This was related conceptually to studies which demonstrated that the spike protein and its specific characteristics could mediate the anterograde axonal transport of virus to the spinal cord. According to the experimental results, demyelinating strains of the MHV coronavirus induced macrophage infiltration of optic nerves, demyelination and axonal loss. These changes were not observed when non-demyelinating strains-created by genetic manipulation of the spike gene itself- were used in the inoculum [70]. The porcine hemagglutinating encephalomyelitis (PHEV) variant of coronavirus (betacoronavirus) is highly neurovirulent. But the neuropathologic mechanism remains poorly understood. It can induce neuropathy by influencing nerve growth factor (NGF)/ tyrosine kinase A receptor (TrkA) endosome trafficking and the

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resultant axonal outgrowth and neurite spouting. PHEV infection induces the expression of miR-142-5p fivefold. This micro RNA regulates the expression of the Ulk-1 mRNA which codes for unc-51-like kinase-1. This enzyme is involved in the control of axon outgrowth and dendrite sprouting and is required for axonal elongation and plasticity. This results in a failure of neurite outgrowth and survival associated with PHEV infection [71, 72]. Viral transport into the CNS from the meninges may also occur via laminin and collagen III fibers between the fourth ventricle and the meninges which create astrocyte-­generated extracellular matrices. These fibers are rapidly upregulated in the early stages of infection by the highly neurovirulent murine coronavirus, cl-2. The virus then invades the ventricle and ventricular wall using the laminin and collagen III fibers as a pathway [73].

Therapeutics Memantine The logical sequel to the finding of glutamate transporter-dependent excitotoxicity was the administration of the N-methyl-D-aspartate antagonist, Memantine (Namenda®). We and other centers use this drug in the treatment of intractable neuropathic pain. Brison et  al., found that the glutamate transporter disruption dependent-excitotoxicity and associated pain behavior in virus-infected mice. This is consistent with the finding of Desforges et al. [14] The drug also improved clinical status related to paralytic disease and motor disabilities by partially restoring the physiological neurofilament phosphorylation state in this same murine model. Brison’s group showed that the drug partially limits both neurodegeneration secondary to excitotoxicity, and viral replication. This latter effect is believed to be mediated via the lysosomotropic effect of the drug [74, 75].  Nase L Protection R Ribonuclease L (RNase L) is part of the innate anti-viral mechanisms that are mediated by the activation of double-stranded RNA-dependent protein kinase (PKR) and the 2′-5′ oligo adenylate synthase (OAS) / ribonuclease L pathways. Activated RNase L cleaves single, 3′ of U-A and stranded RNA found in both viral and cellular RNA.  It thus exerts anti-viral effects via RNA degradation and apoptosis. Paradoxically, it also has the capacity to amplify and prolong expression of anti-­ viral genes and other ISGs. Its contribution to disease severity and viral control depends on the type of virus and the strain within that type. But at this juncture the importance of RNase L lies in its ability to protect against focal infection of microglia/ macrophages in the CNS [76]. Remdesivir Remdesivir, an antiviral that was originally developed for the treatment for Ebola and Marburg viruses. Remdesivir is an adenosine analogue. The drug interferes with viral replication by inhibiting the action of viral ribonucleic acid (RNA)

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replicase. Unfortunately, remdesivir is not significantly effective against the Ebola virus. In 2017, Sheehan et al. demonstrated that remdesivir is effective against both epidemic and zoonotic coronaviruses [77]. When the COVID-19 outbreak started out in China, remdesivir was deployed in clinical trials as one of the possible treatments for the SARS-CoV-2. Remdesivir has been studied in clinical trials outside of China since the pandemic, and preliminary data show that the antiviral confers some degree of protection against the COVID-19 for mild and possibly moderate infections with 31% faster recovery and with a median time of recovery of 11 days compared to 15 days of the placebo group. There is a small improvement in mortality in the remdesivir group of 8% versus 11.6% [78]. The antiviral has not clearly demonstrated effectiveness against severe cases. The preliminary data confirms the expectation that since remdesivir only halts the replication of the virus, therefore, the immune system’s inflammatory response remains unchecked. Remdesivir and bariticinib, a janus kinase (JAK) inhibitor of the subtype JAK1 and JAK2 are in clinical trial for the treatment of COVID-19. Preliminary data suggests that the combination hasten the recovery of the afflicted by one day.

Corticosteroids Corticosteroids have demonstrated both benefits and harms in the setting of pulmonary infections. A meta-analysis of trials concerning the use of corticosteroids on critically ill person with acute respiratory distress syndrome demonstrates statistically significant reduction in all causes of mortality and duration of mechanical ventilation, and an increase in the number of ventilation-free days as compared to placebo [79]. Preliminary data of an open-label study of dexamethasone for the treatment of COVID-19 demonstrates a reduction in all causes of mortality in 28  days of 22.9% vs 25.7% (age-adjusted rate ratio 0.83; 95% CI, 0.75–0.93; P