Academic Press is an imprint of Elsevier 225 Wyman Street, Waltham, MA 02451, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 125 London Wall, London, EC2Y 5AS, UK The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK First edition 2015 Copyright © 2015, Elsevier Inc All Rights Reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-801389-2 ISSN: 1877-1173 For information on all Academic Press publications visit our website at store.elsevier.com CONTRIBUTORS Seena K Ajit Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA E Alfonso Romero-Sandoval Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, South Carolina, USA Carolina Burgos-Vega Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas, USA Julie A Christianson Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA Vaskar Das Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas, USA Gregory Dussor Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas, USA Jill C Fehrenbacher Department of Pharmacology and Toxicology; Stark Neuroscience Research Institute, and Department of Anesthesiology, Indiana University School of Medicine, Indianapolis, Indiana, USA Sarah J.L Flatters Wolfson Centre for Age-Related Diseases, King’s College London, London, United Kingdom Sandrine M Ge´ranton Department of Cell and Developmental Biology, University College London, London, United Kingdom Mohab Ibrahim Department of Anesthesiology, University of Arizona, Tucson, Arizona, USA Kufreobong E Inyang Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas, USA Nathaniel A Jeske Department of Oral and Maxillofacial Surgery, UT Health Science Center, San Antonio, Texas, USA Jungo Kato Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden xiii xiv Contributors Arkady Khoutorsky Department of Biochemistry, Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montre´al, Quebec, Canada Benedict J Kolber Department of Biological Sciences, Duquesne University, Pittsburgh, Pennsylvania, USA Marguerite K McDonald Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA Ohannes K Melemedjian Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Baltimore, Maryland, USA Aaron D Mickle Department of Pharmacology, The University of Iowa Roy J and Lucile A Carver College of Medicine, Iowa City, Iowa, and Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA Durga P Mohapatra Department of Pharmacology; Department of Anesthesia, The University of Iowa Roy J and Lucile A Carver College of Medicine, Iowa City, Iowa, and Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA Jamie Moy Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas, USA Amol Patwardhan Department of Anesthesiology, University of Arizona, Tucson, Arizona, USA Angela N Pierce Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA Steven A Prescott Neurosciences and Mental Health, The Hospital for Sick Children, and Department of Physiology, University of Toronto, Toronto, Ontario, Canada Theodore J Price Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas, USA Reza Sharif-Naeini Department of Physiology and Cell Information Systems Group, McGill University, Montreal, Quebec, Canada Andrew J Shepherd Department of Pharmacology, The University of Iowa Roy J and Lucile A Carver College of Medicine, Iowa City, Iowa, and Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA Justin Sirianni Department of Anesthesiology, University of Arizona, Tucson, Arizona, USA Contributors xv Robert E Sorge Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA Camilla I Svensson Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden Sarah Sweitzer Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, South Carolina, USA Andrew Michael Tan Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven; Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, and Hopkins School, New Haven, Connecticut, USA Keri K Tochiki Department of Cell and Developmental Biology, University College London, London, United Kingdom Stacie K Totsch Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA Megan E Waite Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA PREFACE When we were approached to assemble and edit this volume, we were immediately faced with a dilemma: there are many excellent pain textbooks that already exist, why should we set out to create a new one? After some time, and some perusing of the venerable Textbook of Pain, which has just received a fresh update, it occurred to us that there was indeed room for a new textbook on pain While the existing texts are unquestionably excellent, they largely fail to touch on exciting new areas of research emerging from young investigators in the field There are many young investigators who were on the frontlines of pain research in the laboratories of wellknown figures in the field and now have their own independent laboratories continuing their exciting lines of investigation Therefore, we decided to set out to create a textbook with a slightly different agenda Rather than focusing on specific topics, we decided to assemble a group of the leading young investigators in the field of pain research, give them some guidance on our overall goals, and set them loose to create the chapters they would like to see based on their most exciting new areas of research The title of this book is: “Molecular and Cell Biology of Pain.” A book with such a title could have 100 chapters and take up an entire bookshelf This volume is not meant to be comprehensive, not by any stretch of the imagination, but it is meant to be exciting and new We hope that these are topics that are largely not covered in existing texts in the field but we also hope that these topics will have staying power in the field To that end, the group of investigators assembled for this volume have already agreed, in principle, to update this volume periodically as our research areas continue to progress We hope that the evolution of this title over the coming years will give a sort of history of the research endeavors engaged by the authors of these chapters We are indebted to our mentors, who are many and whom we assume know who they are by this point We are also indebted to the institutions, University of Arizona and University of Texas at Dallas that have given us the opportunity to this work We would like to thank the production team at Elsevier and especially Helene Kabes for her work and collaboration on this project Most importantly, we want to thank our colleagues who agreed to take on this project and without whom this volume most certainly would not exist We value your academic collaboration, your scientific accomplishments at such an early career stage, and your continued friendship xvii xviii Preface Finally, it is our sincere hope that this book will find its way into lecture halls throughout the world We have aimed the material at graduate and medical students and we think it can give these students an interesting snapshot of the forefront of the field If you are a student reading this foreword, we hope you find something in this book that inspires discovery All of us started in your shoes aspiring to learn and make a contribution to mankind through scientific discovery We wish you the best, and we look forward to reading the volume that will be written by the coming generations THEODORE J PRICE GREGORY DUSSOR CHAPTER ONE An Introduction to Pain Pathways and Pain “Targets” Vaskar Das1 Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas, USA Corresponding author: e-mail address: vxd150530@utdallas.edu Contents An Introduction to Pain and Pain Pathways 1.1 Neuropathic pain 1.2 Inflammatory Pain Ion Channels, Receptors, and Other “Targets” for Persistent Inflammatory or Neuropathic Pain 2.1 Ion channels 2.2 Sodium channels 2.3 Calcium channels 2.4 K+ channels 2.5 Receptors 2.6 Purinergic receptors 2.7 Toll-like receptors 2.8 PAR receptors 2.9 Glutamate receptors 2.10 AMPA receptors 2.11 NMDA receptors 2.12 Metabotropic glutamate receptors 2.13 Opioid receptors 2.14 TRPV receptors 2.15 Prostaglandin (prostanoid) E2 2.16 Pronociceptive neurotransmitters Summary Acknowledgments References 9 10 12 12 13 13 13 14 14 15 15 15 16 16 17 17 18 18 18 Abstract The purpose of this chapter is to provide a brief introduction to the anatomy and physiology of pain pathways from peripheral nociceptors to central nervous system areas involved in the perception and modulation of pain This chapter also provides a short introduction to major types of persistent pain: neuropathic and inflammatory persistent pain, and gives an overview of some important molecular targets that are thought to mediate these types of pain These targets, which include ion channels, receptors, and Progress in Molecular Biology and Translational Science, Volume 131 ISSN 1877-1173 http://dx.doi.org/10.1016/bs.pmbts.2015.01.003 # 2015 Elsevier Inc All rights reserved Vaskar Das some neurotransmitters, are further discussed in the context of their relevance as potential drug targets for the better treatment of pain in patients with persistent pain Finally, this chapter introduces several important concepts in pain research that will be primary topics for chapters that come later in the book AN INTRODUCTION TO PAIN AND PAIN PATHWAYS The International Association for the Study of Pain (IASP) has defined pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”1 When asked to describe their pain, individuals variously described it in terms of severity (mild, moderate, severe), duration (acute or chronic), and type (nociceptive, inflammatory, neuropathic).2 Nociceptive pain is the normal acute pain sensation produced by activation of nociceptors in skin, viscera, and other internal organs in the absence of sensitization.3–7 It may occur as a result of mechanical, thermal, or chemical noxious stimulation and is variously described as an aching or throbbing kind of pain.5,6,8,9 Nociceptive pain comprises four main stages: transduction (i.e., action at receptors in the periphery), transmission (i.e., action potentials along axons), perception (i.e., cortical processing of nociceptive input), and modulation (i.e., engagement of descending circuits).4,10–12 Noxious stimuli are first detected by mechanical, thermal, and chemical nociceptors found on specialized nerve endings present in skin (cutaneous), viscera, and other internal or external organs.8,9,13,14 Nociceptive impulses are transmitted from the periphery to the spinal cord via primary afferent nerve fibers which may be unmyelinated or myelinated.3,15–20 The central nervous system (CNS) components of this pathway constitute particular anatomical connections in the spinal cord, brain stem, thalamus, and cortex (the “pain pathway”), linking the sensory inflow generated in high threshold primary afferents with those parts of the CNS responsible for conscious awareness of painful sensations21 (Fig 1) Unmyelinated nerve fibers are small diameter C-fibers with diameters in the range 0.4–1.2 μm.22,23 Myelinated primary afferent nerve fibers are the Að-fibers (2–6 μm diameter), whereas the thinly myelinated nerve fibers are the Aβ-fibers (>10 μm diameter).23,24 Primary afferent C-fibers and Að-fibers are responsible for transmission of noxious stimuli whereas Aβ-fibers transmit innocuous, mechanical stimuli such as touch.21–24 Put simply, nociceptors collect information from noxious stimuli which are transmitted by C-fibers and An Introduction to Pain Pathways and Pain “Targets” Figure Simplified schematic diagram of the pain pathway Pain begins with detection of damage or potentially damaging stimuli by nociceptive neurons in the periphery that can transduce this signal into transmission toward the CNS The first synapse in this pathway is in the dorsal horn, where these projection neurons can send pain-related information onto multiple brain areas Pain perception occurs in the brain and can be modulated by different centers in the brain The brain also sends modulatory inputs back down to the spinal cord to induce pain modulation Að-fibers through the dorsal root ganglia to the superficial laminae I/II of the dorsal horn of the spinal cord.20,23 Að-fibers transmit impulses from the dorsal horn to deeper laminae (III–IV) of the spinal cord and onto higher centers in the brain via the spinothalamic tracts.20 Dorsal horn neurons comprise (i) projection neurons, (ii) local interneurons, and (iii) propriospinal neurons.20,25 Although projection neurons are the primary means for transferring sensory information from the spinal cord to the brain, they are only a small fraction of the total number of cells in the dorsal horn.23,26 Many Vaskar Das projection neurons have axons that cross the midline and ascend to multiple areas of the brain including the thalamus, periaqueductal gray matter, lateral parabrachial area of the pons, and various parts of the medullary reticular formation.27 These neurons are also involved in activation of endogenous descending inhibitory pathways that modulate dorsal horn neurons.26 Activity-dependent synaptic plasticity in the spinal cord that generates postinjury pain hypersensitivity together with the cellular and molecular mechanisms responsible for this form of neuronal plasticity are termed “central sensitization.”21 Neuroplastic changes relating to the function, chemical profile, or structure of the peripheral nervous system are encompassed by the term “peripheral sensitization” and encompass changes in receptor, ion-channel, and neurotransmitter expression levels.28,29 Central sensitization in the spinal cord includes sensitization and disinhibition mechanisms, and supraspinally there are functional changes such as enlargement of receptive fields.30,31 In the CNS, there are also changes in the dynamic interplay between neuronal structures and activated glial cells,30,32,33 a topic covered in depth in Chapter “Nonneuronal Central Mechanisms of Pain: Glia and Immune Response” by E Alfonso Romero-Sandoval and Sarah Sweitzer Following tissue injury and inflammation, vasoactive mediators such as histamine, substance P (SP), serotonin (5-HT), nitric oxide (NO), prostaglandins (PGs), and bradykinin are released which activate nociceptors resulting in nociception.13 This in turn can induce release of pronociceptive neurotransmitters such as SP, calcitonin gene-related peptide (CGRP), dynorphin (Dyn), neurokinin A (NKA), glutamate, adenosine triphosphate (ATP), NO, PGs, and neurotrophins such as brain-derived neurotropic factor (BDNF), from primary afferents either in the periphery or at the first synapse in the dorsal horn of the spinal cord.13,20,22,34,35 More recently, the important role of proinflammatory cytokines (e.g., tumor necrosis factoralpha (TNF-α), interleukin-1β, interleukin-18, etc.) in peripheral and central sensitization mechanisms associated with persistent pain states has begun to be appreciated.36 Many C-fibers express transient receptor potential vanilloid (TRPV1) receptors and hence are sensitive to the vanilloid, capsaicin, which is a highaffinity ligand for TRPV1 receptors.37 TRPV1-expressing C-fibers may be further subdivided into two major classes: (i) those that contain the neuropeptides, SP, and CGRP, express the highaffinity nerve growth factor (NGF) receptor, TrkA, and are developmentally dependent on NGF,34,38,39 and 616 Cytoplasmic polyadenylation element binding protein (CPEB), 419–422, 419f D Damage-associated molecular pattern molecules (DAMPs) acute and protective pain, 270 acute inflammatory disorder, 270–271 chronic pain, 254 cytokine blockade, 270–271 dysregulation, inflammation and immune reactions, 270–271 extracellular matrix, 256 HMGB1 (see High-mobility group box (HMGB1)) HSPs (see Heat-shock proteins (HSPs)) lipopolysaccharide, 254 necrotic cells, 254–256 nociceptive system, 270–271 nociceptors, 270 PAMPs, 254 pathogenic infection, 254–256 physiological conditions, 254–256 plasticity mechanisms, 270 PRRs, 254, 255t purine metabolites (see Purine metabolites) RAGE, 254–256 secretory reticulum-Golgi pathway, 254–256 S100 proteins (see S100 proteins) TNF blockade, 270–271 Dendritic spine dysgenesis mental retardation, 392–393 NSC23766 treatment, 399–400, 401–402 Rac1, 398–400 spinal memory mechanism, 402–403 Dendritic spines dendritic branch, 389, 390f description, 388, 388f in neuropathic pain, 393 in pathology, 392–393 plasticity after peripheral nerve injury, 396 real anomalies on neurons, 389 remodeling in SCI, 394–395, 395f spiny neurons, 389 stubby and thin/mushroom shapes, 389 Index STZ-induced diabetes, 396–397 in synaptic function, 391–392 (see also Long-term potentiation (LTP)) thermal burn injury, 397–398 Diabetic polyneuropathy, 587 Dietary interventions analgesic effect, 456–457 anti-inflammatory properties, 456–457 knee pain, 456 Mediterranean diet, 457–458 NFkB inhibitor, 457–458 randomized control study, 458 rheumatoid arthritis, 456–457 DiGeorge syndrome chromosome region (DGCR8), 219–220, 221f Distal symmetrical polyneuropathy (DSPN), 586 DLPFC See Dorsolateral prefrontal cortex (DLPFC) DNA damage, 489 DNA methylation DNA methyltransferases, 161–162 learning and memory, 162 memory formation, 161f, 162–163 DNA methyltransferases (DNMTs) antagonizing, 173 cortical infusion, 162 DNMT3a and 3b, 154 DNMT3a2 levels, 161 DNMTis, 155 methylation, 154 zinc fingers, 174f Dorsal root ganglia (DRG) neurons, 260, 262–263, 267–268 bladder pain, intraperitoneal (IP) inhibition, 293–294 coexpression analysis, 291–292 colorectal visceral pain, 293–294 group I activity, 292–294 group II activity, 294–295 group III activity, 295–296 intraplantar inflammation, 292–293 mGluR activation, behavioral effects, 292t mGluR expression, 293f mGluR1-positive neurons, 291–292 skin-applied capsaicin, 296 transient receptor potential vanilloid (TRPV1), 293–294 Index Dorsolateral prefrontal cortex (DLPFC), 61–62 Double-knot toxin (DkTx), 81 DRG neurons See Dorsal root ganglia (DRG) neurons Drug development mGluRs, 315–317 TRPA1, 104–105 TRPM8, 98 TRPV1, 90–91 DSPN See Distal symmetrical polyneuropathy (DSPN) Dural afferent activation application, 547 fibroblasts, 547 ion channels ASIC1–ASIC4, 547–548 ASIC blocker amiloride, 548 endogenous activators/sensitizers, 550–551 extracellular pH, 547–548 in vivo electrophysiological recording techniques, 548 mast cell degranulation, 548–549 preclinical studies, 549 TRP channels, 549 TRPM subfamily, 550–551 TRPM8 transcripts, 550–551 TRPV4 activator, 550 Umbellularia californica, 549–550 mast cell degranulation, 547 neuroplasticity, 551–552 primary afferent nociceptors, 546–547 E Endogenous HMGB1 anti-HMGB1 neutralizing antibodies, 260–262 bone cancer model, 262 cyclophosphamide-induced cystitis, 260–262 in db/db mice, 262 endothelial anticoagulant, 260–262 experimental models, 261t glycyrrhizin, 260 hypernociception, 260–262 immunohistochemistry, 260 lumbar spinal extranuclear fraction, 262 naăve mice and rats, 260 617 nerve injury-induced pain, 260 neurodegenerative diseases, 262 neuroinflammation, 262 neurons and astrocytes, 262 neuropathic pain, 260 protein expression levels, 260 satellite cells, 260 Schwann cells, 260 Endothelin receptors, 40 Epigallocatechin gallate (EGCG), 447–448 Epigenetic mechanisms behavioral epigenetics, 150–151 description, 149–150 DNA methylation, 150–151, 153–155 epigenome, 155–156 gene expression in chromatin compaction, 151f genome-environment interactions, 149–150 histone modifications, 152–153 MeCP2 gene, 151 methyl-CpG DNA-binding protein family, 151 miRNAs, 152 molecular level, 150–151 neuroepigenetics, 150–151 and pain (see Pain, epigenetic mechanisms) postmitotic neural function, 150–151 posttranslational modification, 150–151 Rett syndrome, 151 ERK See Extracellular signal-regulated kinase (ERK) ET type A receptor (ETAR), 40 ET type B receptor (ETBR), 40 Eukaryotic initiation factor 4F (eIF4F) complex and initiation, 191–192, 192f CPEB-Maskin-eIF4E, 200 enhancement, 207–208 mRNA cap, 191 NGF-mediated effects, 196 PNI-induced neuropathic pain, 199 Experimental autoimmune prostatitis (EAP) model, 525–526 Extracellular signal-regulated kinase (ERK), 149, 153, 156–157, 158, 418–419, 419f, 420f ERKMnk1-eIF4E pathway, 196 618 Extracellular signal-regulated kinase (ERK) (Continued ) mTOR pathway (see Mechanistic target of rapamycin (mTOR) pathway) phosphorylation, 198–199 Ras-Raf-Mek-ERK signaling, 198–199 S6K1/IRS-1/ERK signaling, 208–209 F Failed back syndrome (FBS), 569t, 578–580 Familial episodic pain syndrome (FEPS), 103 Fibroblast growth factor (FGF2), 477–478 Fibromyalgia, 569t, 580–581 Formalin, irritants, 101 Fragile X mental retardation protein (FMRP), 415–418, 419–421 G GABA receptors astrocytes, 364 benzodiazepines, 364–365 bicuculline/gabazine, 365 gephyrin, 364–365 metabotropic receptors, 366 spinal diazepam, 365–366 GAD See Glutamic acid decarboxylase (GAD) GAD65 See Glutamic acid decarboxylase 65 (GAD65) GAG See Glycosaminoglycan (GAG) γ-aminobutyric acid (GABA) chloride channels, 369–370 chloride regulation, 376 depolarization, 367 downregulation, KCC2, 375 and GAD, 362–363 glycine, 362 succinic semialdehyde, 364 and VGAT, 362–363 GFAP See Glial fibrillary acidic protein (GFAP) Ginger capsaicin injection, 451–452, 452f dysmenorrhea and osteoarthritis, 451–452 inflammatory cytokine activity, 452 TRPA1 channels, 452 Turmeric and curcumin, 452–453 Index Glia activation/reactivity (see Glial activation) chemokines, 336–337 chronic pain research, 328 CNS (see Central nervous system (CNS)) CX3CR1 expression, 336–337 fractalkine, 336–337 GFAP and IL-8, 347–348 glial markers studies, 347–348, 349t glial modulators (see Glial modulators) human vs rodents, 340–344 microglia and astrocyte cells, 348–351 NK1 knockout mice, 335–336 nonneuronal central mechanisms, 347–348 pain patients, 351 peripheral tissue, 335–336 preclinical models, 328 P2X4, P2X7/P2Y12 receptors, 336 rodent models, 335 spinal ED2/CD163, 348–351 spinal NMDA receptor, 335–336 spinal phosphatases, 348–351 TLR-2 activation, 348–351 TLR-4 agonists, 337–338 Glial activation astrocytes, 334 brain-derived neurotrophic factor, 335 cytokines and chemokines production, 334–335 description, 332 GFAP, 334 homeostatic environment, 332 immunostaining, 332–333 MAPKs, 334 microglial cells, 332–333 morphology and expression, 332 NF-kB signaling, 334–335 nociceptive signaling, 332–333 nonhypertrophic, 332 nonphysiological conditions, 332–333 p-ERK in neurons, 334 physiologic/pathologic, 332 p-JNK in astrocytes, 334 p-p38 in microglia, 334 spinal cord astrocytic S-100b, 334 Glial cells in humans astrocyte phenotype, 340–341 chronic conditions, 343–344 619 Index [11C]-(R)-PK11195, 341, 342 CSF and serum, 340, 342 GFAP, 340–341, 343 glial marker expression, 341 HIV-positive patients, 342–343 IL-8 levels, 342 in vitro incubation, 343–344 in vivo imaging approach, 341, 342 neuroimmune pathological conditions, 341 patients with brain trauma, 340–341 proinflammatory/nociceptive cytokine IL-1, 343 rheumatoid arthritis, 343–344 YKL-40, 340 Glial fibrillary acidic protein (GFAP) CNS, 340–341 CSF, 343 glial markers in pain conditions, 349t immunolabeling, 330f, 331f, 333f knockdown, 340–341 nonhuman primates, 345 serum in patients, 340–341 Glial modulators AZD2423, 347 chronic pain conditions, 345 clinical trials, 345, 346t [11C](R)-PK11195-PET, 345 human subject studies, 345 minocycline, 338–339, 345–347 neurodegeneration, 338–339 neuroimmune mechanisms, 347 nonhuman primates, 345 preclinical pain models, 338 propentofylline, 339, 347 rodent/animal models, 347 treatment, chronic pain, 340 Glutamate receptors, 14–15, 33–36, 38–39 Glutamic acid decarboxylase (GAD), 362–364, 363f, 372–373, 374–375 Glutamic acid decarboxylase 65 (GAD65), 166 Glycine receptors bicarbonate flows, 370 bicuculline and strychnine, 374–375 GABAA receptors, 365 gephyrin, 365–366 nicotinic acetylcholine and type-3 serotonin receptors, 365 Glycosaminoglycan (GAG), 521 G-protein-coupled glutamate receptors (mGluRs) cytoplasmic C-terminal domains, 285 dimers, schematic illustration, 286f group I, 286–289 group II, 290 group III, 290 NMDA and AMPA ionotropic glutamate receptors, 285 N-terminal extracellular domains, 285 in pain neuraxis, expression, 286–289, 289f pharmacological agents, targets and names, 285, 287t Grape seed proanthocyanidin extracts (GSPE), 446–447 H HATs See Histone acetyltransferases (HATs) HDAC inhibitors (HDACis) CBP deficient mice, 160 chronic intraperitoneal, 159–160 class II HDACi SAHA, 166 DNMTis, 173 epigenetic drugs, 166 gene array study, 160 hyperacetylate histones, 153 hypersensitivity, 172 inflammatory and neuropathic pain states, 166 Kv4.3 gene, 166–172 memory formation, 159–160 Nav1.8 in DRGs, 166–172 neuropathic injury, 166–172 neuropathic pain models, 166–172 presynaptic GABAergic synaptic function, 166 sodium butyrate, 159 suberoyl anilide hydroxamic acid, 159–160 trichostatin A, 159 valproate, 159 620 Heat-shock proteins (HSPs) DAMPs, 267 extracellular, 266–267 HSP27, HSP70 and HSP90, 267–268 intracellular chaperones, 266–267 lethal-7 miRNA, 268–269 microRNA, 268–269 proinflammatory roles, 267 High-mobility group box (HMGB1) endogenous (see Endogenous HMGB1) inflammatory mediator, 257–258 nociceptive action, 262–263 nociceptive properties, 258–259 structure, localization and mechanisms, 256–257 Histone acetyltransferases (HATs), 153, 160, 164, 166–172 Histone deacetylases (HDACs) See HDAC inhibitors (HDACis) Histone modifications epigenetic mechanisms, 152–153 synaptic plasticity, 157–158 H3K4me3, 155, 174f H3K27me3, 155 HMGB1 See High-mobility group box (HMGB1) Homo sapiens, 221–222 HSPs See Heat-shock proteins (HSPs) Human miRNA Disease Database (HMDD), 222 Hydrogen sulfide, gasotransmitter, 100–101 I IBS See Irritable bowel syndrome (IBS) IC/PBS See Interstitial cystitis/painful bladder syndrome (IC/PBS) IENF See Intraepidermal nerve fiber (IENF) Immune system antagonism/inhibition, 458–459, 459f broccoli, 449–450, 450f caffeine, 454–455 carotenoids, 450–451 cytokines, 438–441 description, 438 diet and inflammation, 443 dietary interventions, 456–458 ginger, 451–453 ginseng, 453–454 Index grains and gluten, 455 grape seed extract, 446–447 green tea extract, 447–448 ketogenic diets, 455–456 obesity and pain, 442 omega-3 fatty acids, 444–445, 445f omega-6 fatty acids, 443–444 rheumatoid arthritis, 445–446 saturated fats, 446 soy products, 448, 449f Inflammation hyperalgesia and allodynia, 63f nociceptors, 62–65 sensitization, MSCs, 64f Inflammatory hyperalgesia abnormal responses, 47 AKAP 79/150, 42–45 β-arrestin, 45–46 homeostatic, 47 human physiology, 32 mediators (see Inflammatory mediators) posttranslational modifications, 32 primary afferent fibers, 32 proinflammatory receptor systems, 32 protein/protein interactions, 42 signaling mechanisms, 40–42 tissue injury, 42 Inflammatory mediators adenosine triphosphate, 32–33 bradykinin receptor, 32–33, 36 calcitonin receptor, 39–40 damaged epithelial cells, 32–33 endothelin receptors, 32–33, 40 glutamate receptors, 33–36, 38–39 neurokinin receptor, 38 nociceptor-originated mediators, 33 peripheral tissue, 33 primary afferent nociceptors, 33–36 prostaglandin receptor, 32–33, 36–37 protease-activated receptors, 39 purinergic receptor, 33–36, 37 RAMP1, 39–40 receptors expression, 33, 34t sensitization, 33–36 serotonin receptor, 37 somatosensory and chemical activation, 32–33 tyrosine kinases, 38 621 Index Inflammatory pain, 7–9 Inflammatory thermal hyperalgesia, 93 Inhibition See Synaptic inhibition Injured tissue ATP and collagen, 188–189 axons, 189 collagenous, 189 extracellular matrix, 189 lacking nociceptive sensitization, 189–190 mast cells, 188–189 NGF and ECM proteins, 189 peripheral nervous system, 189 repair and regeneration mechanisms, 188–189 Schwann cells, 189 with/without nociceptive sensitization, 189–190 Interstitial cystitis/painful bladder syndrome (IC/PBS) adult-onset disorder, 520 bladder urothelial dysfunction, urine metabolites, 521 childhood sexual/physical abuse, 520–521 dimethyl sulfoxide, 519–520 GAG, 521 infection/organic disease, 519–520 intrathecal administration, 521 intravesicular mustard oil application, 520–521 luminal barrier integrity, 521 mast cell infiltration, 522 metabotropic glutamate receptors, 522 signal transduction pathways, 522 urine biomarkers, 520 Intraepidermal nerve fiber (IENF), 479–480, 482 Ion channels, 9–10, 489–491 Irritable bowel syndrome (IBS), 569t, 581–582 adverse events, infancy/childhood, 517 bowel symptoms, 517 colorectal sensitivity, 517–518 functional pain disorders, 516–517 neonatal development, 519 NGF, 518–519 nonpelvic functional pain disorders, 516–517 Rome III criteria, 516–517 WAS, 517–518 Irritants, 101 Isolectin B4 (IB4), 294–295 K KCC2 See Potassium-chloride cotransporter (KCC2) K+ channels, 12–13 L Lipopolysaccharide (LPS), 256–257, 260–263, 267–268 Long-term potentiation (LTP) definition, 391 downstream kinases, activation of, 391 induction protocols, 391–392, 514–515 M Mammalian noncoding RNA-disease database (MNDR), 222 MAPKs See Mitogen activator protein kinases (MAPKs) MCP-1 See Monocyte chemoattractant protein-1 (MCP-1) Mechanical allodynia action potential threshold, 62–65 hyperalgesia, 62–65 innocuous stimuli, 62–65 MSCs, 62–65, 63f voltage-gated ion channels, 62–65 Mechanistic target of rapamycin complex (mTORC1) and ERK, 418–419 rapamycin/polyadenylation inhibitor cordycepin, 421–422 sensory neurons, 418 Mechanistic target of rapamycin (mTOR) pathway de novo protein synthesis, 204–205 4E-BP2 and eIF2α pathways, 208 inhibition and nociception, 198–199, 208–209 mTORC1 and mTORC2, 191–192 peripheral inflammation- and injuryinduced activation, 205–206 622 Mechanistic target of rapamycin (mTOR) pathway (Continued ) PI3K-AKT-mTORC1 pathway, 194, 196 spinal neuronal sensitization, 207–208 translation initiation, 193f Mechanosensation endothelial cells, 54–55 planet, 54–55 primary function, 54–55 supraoptic nucleus, 54–55 thigmotropic and thigmonastic behaviors, 54–55 Mechanosensitive ion channels (MSCs) across species, 54f bona fide MSC, 57–58 Caenorhabditis elegans, 57–58 candidate proteins, identification, 57–58 environment, 53–54 Escherichia coli, 57–58 gating mechanisms, 59–60 mechanical allodynia, 62–65 nociceptors (see Nociceptors) noxious mechanical inputs, 60–62 physiological functions, 53–54 Piezo2, 58–59 potassium, 65 Mechanotransduction, 53–54, 57–58, 62–65 MeDIP-Seq See Methylated-DNA immunoprecipitation (MeDIP-Seq) Memory DNA methylation (see DNA methylation) DNA methyltransferases, 161–162 environmental adaptation, nervous system, 160 G9a/GLP histone methyltransferase complex, 160 genetic modification, HDACs expression, 159 HDAC inhibitors, 159–160 histone acetylation, 158–159 synaptic plasticity, 160 Ted Abel’s group, 160 Messenger RNA (mRNAs) decapping/repression, 202 eIF4F complex, 191, 192f, 202 eukaryotic mRNA 50 cap structure, 192f FMRP, 201 Index mGluR1-mediated activation, 201 RBP, 201 RNP granules, 202 30 UTR and poly-A tail, 200, 201f Metabotropic glutamate receptors (mGluRs), 15–16, 38–39 activity in brain, 307–314 in brainstem and brain, 302–307 cell-signaling cascades, 284–285 drug development, 315–317 G-protein-coupled glutamate receptors, 284–290 presynaptic and postsynaptic neurons, 290–291 role, 284 spinal cord (secondary sensory neurons and interneurons), 296–302 Methylated-DNA immunoprecipitation (MeDIP-Seq), 156 5-Methylcytosine (5mC), 153–154, 156 mGluR activity in brain in amygdala, 307, 308t in cortex, 307, 309t group I activity, 309–312 group II activity, 312–313 group III activity, 313–314 in thalamus, 307, 307t Microglia astrocytes, 329 (see also Astrocytes) AZD2423, 347 carbon-11 ([11C]-(R)-PK11195), 341 CCR3/CD11b, 332–333 CSF, 343–344 CX3CR1 receptor, 336–337 homeostatic environment, 332 ibudilast, 339 immune surveillance and orchestrate, 328–329 and neuronal interactions, 347 NK1 receptors, 335–336 p-p38, 334, 338–339 propentofylline, 339 purinergic receptor, 336 P2X4, P2X7/P2Y12 receptors, 336 rat spinal cord (see Rat spinal cord) TLR-2 agonist, 348–351 TLR-4 agonist, 337–338 YKL-40, 340 623 Index MicroRNAs (miRNAs), 152, 163–164 biogenesis, 218–220 challenges in research, 242–244 chronic pain conditions, 244 circulating miRNAs, 226–229 exosome biogenesis, 226–229 extracellular, 244 genomic location, 220 nomenclature, 221–222 and pain (see Pain) quantification and functional studies, 223–225 seed sequence, 218 targets, 222–223 30 UTR, 218 Microtubule anticancer efficacy, 494 bortezomib, 494 depolymerizing/destabilizing agents, 475–476 MTAs (see Microtubuletargeting agents (MTAs)) posttranslational status, 494 β-tubulin, 475–476 Microtubuletargeting agents (MTAs) classes, 475–476 depolymerizing/destabilizing agents, 475–476 microtubule, 494 neuronal sensitivity, 476 polymerizing/stabilizing agents, 475–476 taxanes, 476 β-tubulin subunits and, 475–476 vinca alkaloids, 476 Middle meningeal artery (MMA), 547 Migraine, 569t, 583–584 ASICs and TRPs, 557 BDNF, 556 CGRP and synaptic plasticity, 554–555 dural afferent activation (see Dural afferent activation) head pain, 540 individual patients, 542 intracranial pressure, 540–542 ion channels, 547–551 mechanosensitivity, 557–558 meningeal afferent system, 544–545 nausea and vomiting, 540–542 neuroplasticity (see Neuroplasticity) nociceptive system, 557 pathological condition, 540 pathophysiology, 545–546 phases, 540–542 prophylactic agents, 557 scotomas, 540–542 treatments, 543–544 triggers, 542 Mineralocorticoid receptor (MR), 513–514 Mitochondrial dysfunction, 486–488 Mitogen activator protein kinases (MAPKs), 149, 153, 156–157, 158, 334–335, 342–343 MMA See Middle meningeal artery (MMA) Monocyte chemoattractant protein-1 (MCP-1), 334–335, 336–337, 340 Monosodium urate crystals (MSU), 270 μ opioid receptors (MORs), 423–424 MR See Mineralocorticoid receptor (MR) MSU See Monosodium urate crystals (MSU) MTAs See Microtubuletargeting agents (MTAs) mTORC1 See Mechanistic target of rapamycin complex (mTORC1) Multiple noxious stimuli, 74 Multiple sclerosis (MS), 569t, 584–585 N N-acetylcysteine (NAC), 488–489 NAD See Nicotinamide adenine dinucleotide (NAD) National Cancer Institute (NCI), 478–479 National Institutes of Health chronic prostatitis symptom index (NIH-CPSI), 524–525 Neonatal intensive care unit (NICU), 515–516 Nerve growth factor (NGF), 38, 149, 492–493, 518–519, 520, 522, 525 Neurokinin receptor, 38 Neuropathic pain See also Persistent inflammatory pain dendritic spines, 393 diabetic, 396–397 IASP definition, inflammatory and neuroimmune mechanisms, 624 Neuropathic pain (Continued ) pathobiology, peripheral nerve injury, 6–7 persistent ongoing pain, 6–7 Rac1 inhibition, mode of action, 401–402 rodent models, 5–6 spinal memory mechanism, 402–403 thermal injury, 397–398 zoster virus-induced, Neuroplasticity chemical stimulation, dural afferents, 553–554 cutaneous allodynia, 552 cytokines, neuropeptides and growth factors, 551–552 episodic migraines, 552 facial allodynia, 551–552 headache, 553–554 mechanism, 554 neurotransmitters, 554 pain-sensing fibers, 553 peripheral and central nervous systems, 552 TNC and activation, 551–552 trigeminovascular activation, 551–552 Neurotransmitters, 362–364 Neurotrophic factors embryonic neurons, 492–493 neurotrophin, 492–493 NGF, 492–493 paclitaxel and cisplatin therapy, 492–493 preclinical animals, 492–493 sensory neurons, 492–493 NGF See Nerve growth factor (NGF) Nicotinamide adenine dinucleotide (NAD), 153 NICU See Neonatal intensive care unit (NICU) NIH-CPSI See National Institutes of Health chronic prostatitis symptom index (NIH-CPSI) Nitroxidative stress chemotherapeutics, 488–489 N-acetylcysteine (NAC) functions, 488–489 ROS and RNS, 488–489 TEMPOL, 488–489 Index NKCC1 See Sodium-potassium-chloridecotransporter (NKCC1) N-methyl-D-aspartate receptor (NMDA) receptor, 15, 156–157, 158 Nociception capsaicin’s excitatory effects, 78 noxious stimuli, encoding and processing, 74 and pain, 74, 77–78, 91–92 TRPV1, activation/potentiation, 87–88 Nociceptors AMPK activation pathway, 418–419, 420f anisomycin/rapamycin, 421–422 brain regions, 416 CPEB, 419–421 Drosophila larvae, 57 electrophysiological studies, 55–57 FMRP, 416–418 gene expression, 416 genetic studies, 57 hyperalgesic priming models, 418 microfluidic devices, 416–418, 417f MSCs, 55–56 mTORC1 and ERK, 418–419 neurons, 55 nociceptor peripheral terminals, 55–56 originated mediators, 33 pharmacological characterization, 56–57 postsynaptic density, 416–418, 417f potassium, 65 protein–protein interaction, 416–418 rheumatoid arthritis and osteoarthritis, 55 ribosomes, dendritic spines, 415–416 RNA binding proteins, 419–421 single-channel recordings, 56–57 translational control pathways, 418, 419f TRPV1, 55–56 whole-cell voltage-clamp, 56–57 Nociceptor sensitization, 87 Nonsteroidal anti-inflammatory drugs (NSAIDs), 543 Nucleus Raphe Magnus (NRM), 164–166 O Opioid receptors, 16 Oral squamal cell carcinomas (OSCCs), 40 Osteoarthritis, 55, 61–62, 65 Index Oxaliplatin acute behavioral effect, 480–482 bevacizumab, 477–478 Ca2+/Mg2+ infusions, 490–491 CIPN, 487 cisplatin, 476–477 ion channel dysfunction, 490–491 patients, 477 treatment, 477 P Paclitaxel acute pain syndrome, 476 ALCAR, 486–487 application, 483–484 CCL2/CCR2 pathway, 491–492 CIPN, 480, 489 NGF levels, 492–493 oxaliplatin, 480–482 pain and dysesthesia, 487 SNCV, 482 treatment, 483–484 TRPV1-mediated release, 484–485 Pain acute syndrome, 476 in bone cancers, 87 CFA-induced inflammatory, 93 CIPN patients, 478–479 epigenetic mechanisms acute to chronic pain, 175–176 DNA methylation, 172–173 early life injury, 176 epigenetic machinery and epigenome, 164–166 HDACs and HATs, 166–172 in infancy, 150f miRNA expression, 163–164 molecular and behavioral response, 163–164 treatment, persistent pain, 173–175 IENF loss, 479–480 inflammatory, 492–493 miRNAs, 218–220, 221–225, 226–244 olesoxime on paclitaxel-induced, 487 oxaliplatin, 477 sensory TRP channels (see Transient receptor potential (TRP) channel) TRPA1 role, 103–104 625 TRPM8 role, 97–98 TRPV1, 86–88 Pain and pain pathways activity-dependent synaptic plasticity, 2–4 C-fibers, 4–5 definition, inflammatory pain, 7–9 International Association for the Study of Pain (IASP), neuropathic pain, 5–7 nociceptive, 2–4 pronociceptive neurotransmitters, schematic diagram, 3f tissue injury and inflammation, TRPV1-expressing C-fibers, 4–7 vasoactive mediators, Painful peripheral neuropathy, 585 Pain in brainstem and brain anatomic loci, 302–303 group I activity, 305 group II activity, 306 group III activity, 306–307 mGluR activation, 303–304, 304t mGluR expression, 302–303, 303f Pain memory acute and chronic inflammatory pain, 412–413 chronic neuropathic pain, 412 clinical experience, 429 hippocampus and cerebral cortex, 412–413 hyperalgesic priming, 413–414 mechanisms, 413–414 neuronal plasticity, 412 pain amplification, 412 peripheral nervous system, 413 peripheral nociceptor (see Nociceptors) phantom limb pain, 413 spinal dorsal horn (see Spinal dorsal horn) Pain neuraxis, mGluRs analysis in brainstem and brain, 302–307 conventional knockout and systemic effects, 314–315 mGluR activity in brain, 307–314 mGluR drug development, 315–317 periphery, 291–296 presynaptic and postsynaptic neurons, 290–291 626 Pain neuraxis, mGluRs analysis (Continued ) spinal cord (secondary sensory neurons and interneurons), 296–302 Pain plasticity, 414–415 Pathogen-associated molecular pattern molecules (PAMPs), 254 Pattern recognition receptors (PRRs), 254, 255t, 270–271 Peripheral nerve injury dendritic spine remodeling, 396 NSC23766 treatment, 401–402 and SCI, 397 STZ-induced diabetes, 397 Peripheral neuropathic pain chemoprotectant agents, 585–586 CIPN, 585 diabetic polyneuropathy, 587 distal symmetrical polyneuropathy (DSPN), 586 DRG neurons (see Dorsal root ganglia (DRG) neurons) factors, 585 in HIV, 586 hyperglycemia, 587 mechanisms and treatments, 569t nucleoside reverse transcription inhibitors, 586 viral antigens, 586 Persistent inflammatory pain AMPA receptors, 15 calcium channels, 12 glutamate receptors, 14–15 ion channels, 9–10 K+ channels, 12–13 metabotropic glutamate receptors, 15–16 NMDA receptors, 15 opioid receptors, 16 PAR receptors, 14 pronociceptive neurotransmitters, 17–18 prostaglandin (prostanoid) E2, 17 purinergic receptors, 13 receptors, 13 sodium channels, 10–11 toll-like receptors, 13–14 TRPV receptors, 16–17 Persistent postsurgical pain, 569t, 588–589 Index PET See Positron emission tomography (PET) Phantom limb pain (PLP), 569t, 589–590 PHN See Postherpetic neuralgia (PHN) Phosphatidylinositol-bis-phosphate (PIP2), 82–83 Phosphodiesterase D3 (PDE4D3), 43 Phospholipase C-β (PLC-β), 84–85 Platinum-containing agents, 476–477 PLP See Phantom limb pain (PLP) Pore loop, 74–75 Positron emission tomography (PET), 341, 345 Postherpetic neuralgia (PHN), 569t, 590–591 Potassium-chloride cotransporter (KCC2) and NKCC1, 369–370 spinal neurons, 375 Presynaptic TRPV1, 79 Pronociceptive neurotransmitters, 17–18 nerve growth factor, 18 nitric oxide, 17 Prostaglandin (prostanoid) E2, 17 Prostaglandin receptor, 32–33, 36–37 Protease-activated receptors (PAR), 14, 39 Proteasome inhibitors, 477 Protein kinase Ce (PKCe), 175–176 Protein kinase Mz (PKMz), 175–176 PRRs See Pattern recognition receptors (PRRs) Purine metabolites ATP, 269–270 description, 269 uric acid, 270 Purinergic receptors, 13, 33–36, 37 R RA See Rheumatoid arthritis (RA) Rat spinal cord cellular interactions, glial cells, 331f glial cells and neurons, physical interactions, 330f microglia and astrocytes, physical interactions, 331f naăve and peripheral nerve injury conditions, 333f Receptor activity-modifying protein (RAMP1), 39–40 Index Receptor for advanced glycation end products (RAGE), 254–256, 257, 258–259, 259f, 263, 266 Resiniferatoxin (RTX), 81 Rheumatoid arthritis (RA), 569t, 591 RNA-induced silencing complex (RISC), 219–220, 230 S SAHA See Suberoyl anilide hydroxamic acid (SAHA) Sensitization, 583 Sensory nerve conduction velocity (SNCV), 482 Serotonin and calcitonin gene-related peptide, 583 Serotonin receptor, 37 Sodium channels, 10–11 Sodium-potassium-chloride-cotransporter (NKCC1) and KCC2, 375–376 neuronal chloride homeostasis, 369–370 Spinal cord astrocytic S-100b, 334 glial fibrillary acidic protein, 334 HIV-positive patients, 342–343 MAPKs, 334 mGluRs analysis acute nociception, 296–297 dynamic modulation, 296–297 group I, 297–300 group II, 300–301 group III, 301–302 mGluR activation, behavioral effects, 297t mGluR1 and mGluR5 activation, 300 postsynaptic modulators, 299–300 microglial CCR3/CD11b, 332–333 microglial p-p38, 338–339 neuronal excitatory milieu, 335 NMDA receptor hyperactivity and neuronal sensitization, 334–335 peripheral lymphocytes and monocytes, 329 rat spinal cord (see Rat spinal cord) Spinal cord injury (SCI) dendritic spine remodeling, 394–395 627 density and altered spine distribution, 394–395, 395f NSC23766 treatment, 399–400, 401–402 and peripheral nerve injury, 397 Spinal dorsal horn acetazolamide and benzodiazepines, 377 allodynia, 422–423 atypical PKCs and BDNF, 424–427 bicarbonate efflux, 370 capsaicin and formalin, 423, 427–429 central sensitization, 422–423 chloride dysregulation, 376–377 chloride flows, 367 chloride regulation, 368–369, 368f ClC-2 channels, 368–369 excitatory interneurons, 373–374 GABAA and glycine receptors, 366 Gate Control Theory, 362 GHK equation, 366–367 hippocampal/cortical memory mechanisms, 427 hyperalgesic priming paradigm, 427–429 impaired synaptic transmission vs impaired inhibitory effect, 376–377 inhibitory neurons, 372–373 intracellular chloride concentration, 370 ion concentration, 367–368 late phase LTP (late-LTP) and reconsolidation, 427, 428f long-lasting memory, 427 microglia and inflammation, 376 MORs, 423 Nernst equation, 366–367 nerve injury/inflammation, 377 neuropathic pain, 373–374 opioid-dependent mechanisms, 423–424 perforated patch technique, 370 potassium-chloride cotransporter (KCC2), 369 sodium-potassium-chloridecotransporter (NKCC1), 369–370 superficial dorsal horn, 372, 373f Spinal nerve ligation (SNL) model, 231–234, 235 Spiny neurons, 389 S100 proteins calcium-binding EF-hand motifs, 264 characterization, 264 628 S100 proteins (Continued ) DAMP molecules, 264 intracellular functions, 264 S100A8 and S100A9, 264–265 S100B, 265–266 Streptozotocin (STZ), 396–397, 401 Stress child maltreatment, 515–516 comorbidity, 515–516 NICU, 515–516 NMS, 516 Suberoyl anilide hydroxamic acid (SAHA), 166, 167t Substance P (SP)-expressing C-fibers, 8–9 Synaptic inhibition disinhibition, 376 GABAA receptors, 371 glycinergic transmission, 375 inhibitory neurotransmitters (see Neurotransmitters) KCC2 and NKCC1, 375–376 nerve injury, 374–375 pain processing, 374–375 Synaptic plasticity acute and prolonged pain states, 149 α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid, 156–157 brain-derived neurotrophic factor, 149 cAMP response elementbinding protein, 156–157 epigenetic mechanisms (see Epigenetic mechanisms) epigenome, 163 extracellular signal-regulated kinases, 149 histone modifications, 157–158 learning and memory, 149 memory formation, 156–157 (see also Memory) mitogen-activated protein, 149 neuroepigenetics, 149 neurotrophins, 149 N-methyl-D-aspartate receptor, 156–157 pain, 149 posttranslational regulation, 156–157 T Taqman low-density array (TLDA), 223–224 Thermal burn injury, 397–398 Index TLR signals See Toll-like receptor (TLR) signals TNC See Trigeminal nucleus caudalis (TNC) TNF See Tumor necrosis factor alpha (TNF-α) Toll-like receptor (TLR) signals, 13–14, 491–492 Total internal reflective fluorescence-Forster resonance energy transfer (TIRF-FRET), 44–45 Total neuropathy score (TNS), 478–479 Transcriptional activator-like effectors (TALENS), 174–175 Transient receptor potential (TRP) channel cytoplasmic regions, structural–functional features, 77f functional, 76f, 77–78 in phototransduction, 74 tetramers of 6-transmembrane (6-TM), 74–75 thermosensing nociceptive, 75f TRP box, 75–77 Transient receptor potential subfamily A member (TRPA1) in autonomic reflexes and disorders, 99–100 channel expression and function modulation, 102–103 channel, functional properties, 100–102 cold-sensing ion channel, 102 drug development targeting, 104–105 human, 101 human lung fibroblasts, 98–99 in pain conditions, 103–104 sensory afferents expressing, 99 structure, 100 Transient receptor potential subfamily A member (TRPA2) phagocytosis, 91 in rodent sensory neurons, 91 Transient receptor potential subfamily A member (TRPA3), 93 antagonists, 91–92 camphor, 91–92 expression, 91–92 rodent PNS and CNS neurons, 91–92 sequence homology cloning, 91–92 629 Index Transient receptor potential subfamily A member (TRPA4) activation, 92–93 in DRG and TG neurons, 92–93 energy homeostasis maintenance, 92–93 irritable bowel syndrome (IBS), rodent model, 92–93 in neurons and muscles, 92–93 pancreatitis, rodent model, 92–93 polyunsaturated fatty acids (PUFAs), 92–93 Transient receptor potential subfamily A member (TRPA8) channel expression and function modulation, 96 in cold hypersensitivity, 98 drug development targeting, 98 functional properties, 95–96 knockout mice, 97–98 in nervous system, expression and distribution, 94 in pain conditions, 97–98 in prostate epithelial cells, 94 role, 95–96 structure, 94–95 Transient receptor potential vanilloid (TRPV1), 16–17, 55–56, 58 activation, 78 capsaicin’s excitatory effects, 78 channel desensitization, 86 channel expression and function, modulation, 83–86 channel, functional properties, 80–83 cryo-EM structure, 81–82 drug development targeting, 90–91 in nervous system, expression and distribution, 78–79 in pain conditions, 86–88 phosphorylation, 84–85 in physiological and pathological conditions, 88–90 in sensory neurons, 78 S4 segment, voltage-dependent movement, 81–82 structure, 79–80 toxins VaTx and DkTx, 81–82 Translational control capsaicin, 204–205 definition, 191 formalin, 204–205 long-term depression (LTD), 203–204 long-term potentiation (LTP), 203–204 mechanisms, 203 mTOR pathway, 203–204 nociceptive pathways, 203 opioid-induced hyperalgesia, 206 peripheral C-fiber activation, 204–205 reconsolidation, 207 sensory neurons, 203 spinal LTP, 203–204 spinal neuronal sensitization, 207–208 spinal neurons, 205–206 spinal nociceptive circuit, 203 spinal nonneuronal cells, 206–207 synaptic plasticity in CNS, 203–204 Trigeminal neuralgia, 569t, 591–592 Trigeminal nucleus caudalis (TNC), 551–552, 553–554, 557–558 Trigeminovascular system, 583 TRPA1 See Transient receptor potential subfamily A member (TRPA1) TRPV1 See Transient receptor potential vanilloid (TRPV1) Tumor necrosis factor alpha (TNF-α), 334–335, 339, 342–343 Tyrosine kinases, 38 U 30 untranslated region (30 UTR) lin-14 30 UTR, 218–219 mRNAs, 218 target mRNAs, 222–223 V Vanilloid receptor subtype-1 (VR1), 78 Vanillotoxins (VaTx), 81 Vascular endothelial growth factor (VEGF), 477–478 Vertebroplasty, 574 Vesicular GABA transporter (VGAT), 362–364, 363f Vinca alkaloids, 476, 489–490 Visceral pain, 568 Voltage-gated calcium channels (VGCC), 630 Vulvodynia adult female mice, 523 allodynia, 522–523 antidepressant and anticonvulsant medication, 523 erythema, 522–523 idiopathic pain disorders, 523 IL-1RA, 524 leukocyte infiltration, 523–524 mood disorders, 523 neurologic disorder, 522–523 Index proinflammatory cytokines IL-1, 524 tumor necrosis factor-α, 524 W Water avoidance stress (WAS), 517–518 Whole-genome bisulphite sequencing (WGBS), 156 Z Zif268 gene, 156–157, 158, 163 ... Scaffolding and Signaling Pathways in Inflammatory Pain by Jeske Nathan.” Inflammatory mediators including protons, 5HT, histamine, adenosine, bradykinin, prostaglandin E2 (PGE2), NO, IL-1, TNF-α, interleukin-6... spontaneous pain and plasticity in the dorsal horn and brain that underlies clinical features including allodynia and hyperalgesia An Introduction to Pain Pathways and Pain “Targets” proinflammatory... Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in