The Nociceptive Membrane

Membranes are essential cellular organelles. They not only define cells and other organelles, but also are critical in the cell function by selectively regulating the passage of molecules by acting as a matrix for other signaling molecules, and as conduits of information transfer between the external environment and the cell interior. This series was originally added in 1970 and has since provided a systematic, comprehensive, and rigorous approach to specific topics relevant to the study of cellular membranes. Each volume is a guest edited compendium of membrane biology. This series has been a mainstay for practicing scientists and students interested in this critical field of biology. Articles covered in the volume include History of Ion Channels in the Pain Sensory System; Historical Overview; TRPV1, a Polymodal Sensor in the Nociceptor Terminal; Nociceptive Signals to TRPV1 and its Clinical Potential; Gating, Sensitization and Desensitization of TRPV1; TRP Channels as Thermosensors; ASIC Channels; P2X Receptors in Sensory Neurons; Voltage-Gated Sodium Channels and Neuropathic Pain; Voltage-Gated Potassium Channels in Sensory Neurons.

1;Cover Page;1 2;Contents;6 3;Contributors;12 4;Foreword;16 5;Previous Volumes in Series;18 6;Chapter 1: Historical Evolution of Pain Concepts;21 6.1;I. Overview;21 6.2;II. Pain: A Function of Brain Matter in the 17th Century;22 6.3;III. Physics and Pseudophysics in Pain Treatment of the 18th Century;24 6.4;IV. Discoveries in the 19th Century Relating to Pain;27 6.4.1;A. Psychophysics of Experimental Pain;27 6.4.2;B. The Discovery of Ether Anesthesia;28 6.4.3;C. The Discovery of Local Anesthesia;30 6.4.4;D. Isolation and Synthesis of Analgesic Substances;31 6.5;V. Challenges and Changing Pain Concepts During the 20th Century;34 6.5.1;A. Clinical Research on Pain;34 6.5.2;B. Experimental and Clinical Neurophysiology of Pain;36 6.5.3;C. New Vistas on Pain Since 1950;37 6.6;References;38 7;Chapter 2: History of Ion Channels in the Pain Sensory System;41 7.1;I. Introduction;42 7.2;II. The TRPV1/VR1 Capsaicin Receptor;43 7.2.1;A. Discovery of Capsaicin Desensitization;43 7.2.2;B. Prediction of the Capsaicin Receptor on C-Polymodal Nociceptors;45 7.2.3;C. Mechanism of Sensory Blockade Induced by TRPV1 Agonists;54 7.2.4;D. Discovery of the Capsaicin-Gated Cation Channel;57 7.3;III. Voltage-Gated Na+ Channels;58 7.3.1;A. Summary of Early Observations on Voltage-Gated Na+ Currents in Primary Afferent Neurons;58 7.3.2;B. Identification and Characterization of Na+ Channels in Primary Afferent Neurons;60 7.3.3;C. Alterations in Expression and Function of Na+ Channels in DRG Neurons Under Neuropathic Conditions;64 7.3.4;D. Influence of Neurotrophic Factors on Na+ Channel Expression and Na+ Currents in DRG Neurons;68 7.3.5;E. Effect of Inflammatory Mediators and Conditions on Expression and Function of Na+ Channels in Primary Sensory Neurons;69 7.4;IV. Nicotinic Acetylcholine Receptors;71 7.5;V. Serotonin Ionotropic Receptor;72 7.6;VI. Glutamate Ionotropic Receptors, Proton-Gated Ion Channels (ASIC2, ASIC3), and P2X Purinoceptors;73 7.6.1;A. NMDA, AMPA, and Kainate Glutamate Rece
ptors;73 7.6.2;B. Proton-Gated Ion Channels;74 7.6.3;C. P2X Receptors;74 7.7;VII. Initiation of Impulses at Nociceptors;75 7.8;References;79 8;Chapter 3: The Nociceptive Membrane: Historical Overview;93 8.1;I. Introduction;93 8.1.1;A. Nociceptors;93 8.1.2;B. Morphology of Nociceptors;95 8.1.3;C. Peripheral Sensitization of Nociceptors;96 8.1.4;D. Transduction Molecules and Ion Channels in Nociceptors;96 8.2;II. Nociceptive Transduction;97 8.2.1;A. Transduction of Noxious Mechanical Stimuli;99 8.2.2;B. Transduction of Acidic Stimuli;101 8.2.3;C. Transduction of Noxious Thermal and Chemical Stimuli;102 8.2.4;D. Itch Sensation;114 8.3;III. Sensitization of Nociceptors;114 8.3.1;A. Growth Factors;115 8.3.2;B. Noxious Stimuli;115 8.3.3;C. Signal Transduction Pathways;116 8.4;IV. Role of Voltage-Gated Sodium and Potassium Channels in Peripheral Sensitization;117 8.4.1;A. Voltage-Gated Sodium Channels;117 8.4.2;B. Voltage-Gated Potassium Channels;118 8.5;References;119 9;Chapter 4: TRPV1: A Polymodal Sensor in the Nociceptor Terminal;133 9.1;I. Discovery and Cloning of the Vanilloid Receptor;134 9.1.1;A. Study of Pungent Peppers Leads to Characterization of a "Vanilloid" Receptor;134 9.1.2;B. Molecular Cloning of a Vanilloid Receptor, TRPV1;137 9.2;II. TRPV1 Exhibits a Highly Specific Expression Pattern;139 9.3;III. Activators and Inhibitors of TRPV1;140 9.3.1;A. Diverse Chemical Activators of TRPV1;140 9.3.2;B. Chemical Antagonists of TRPV1;142 9.3.3;C. TRPV1 is the First Heat-Gated Ion Channel to be Identified;143 9.3.4;D. Structure-Function Relationships for Agonist/Antagonist Interaction with TRPV1;145 9.4;IV. Regulation of TRPV1;147 9.4.1;A. TRPV1 Desensitization;148 9.4.2;B. TRPV1 Sensitization;151 9.4.3;C. Convergence of Sensitizing and Desensitizing Influences on TRPV1;154 9.5;V. Contributions of TRPV1 to Acute Nociception and Hyperalgesia;154 9.5.1;A. Endogenous TRPV1 and the Detection of Vanilloid Compounds by Nociceptors;155 9.5.2;B. Endogenous TRPV1 and the Det
ection of Protons by Nociceptors;155 9.5.3;C. Endogenous TRPV1 and Nociceptor Responses to Heat;157 9.5.4;D. TRPV1 and Thermal Hyperalgesia Following Inflammation;159 9.5.5;E. TRPV1 and Thermal Hyperalgesia Following Nerve Injury;161 9.5.6;F. Role for TRPV1 in Mechanical Nociception and Mechanical Hyperalgesia;161 9.6;VI. Concluding Remarks;162 9.7;References;162 10;Chapter 5: Nociceptive Signals to TRPV1 and its Clinical Potential;171 10.1;I. Introduction;172 10.1.1;A. Effect of Capsaicin on Sensory Neurons;172 10.1.2;B. Biophysical Properties of Capsaicin-Activated Channels;174 10.1.3;C. TRPV1: A Cloned Capsaicin-Activated Channel;175 10.1.4;D. Capsaicin Binds TRPV1 from the Cytosolic Side;175 10.2;II. Endogenous Activators of TRPV1;176 10.2.1;A. Anandamide;176 10.2.2;B. N-Arachidonyl-Dopamine;177 10.2.3;C. Metabolic Products of Lipoxygenase;178 10.2.4;D. Binding Capacity of 12-HPETE to TRPV1;178 10.2.5;E. Comparison of 3D Structures of Capsaicin with 12-HPETE;179 10.3;III. The TRPV1 Ligand-Binding Sites;181 10.3.1;A. Transmembrane Domain 3 (TM3) Region;181 10.3.2;B. Ligand-Binding Sites in the N- and C-termini;183 10.4;IV. Nociceptive Signals to TRPV1;184 10.4.1;A. Bradykinin Signaling Pathway to TRPV1;184 10.4.2;B. 20-HETE Action on TRPV1;186 10.4.3;C. Histamine Intracellular Signals in Sensory Neurons;187 10.5;V. TRPV1 Antagonists: A New Class of Analgesics;189 10.5.1;A. Capsazepine;189 10.5.2;B. SC0030;190 10.5.3;C. Iodo-Resiniferatoxin;191 10.5.4;D. High-Throughput Screening for TRPV1 Antagonists;191 10.5.5;E. SB-366791, AMG9810, and their Analogs;192 10.5.6;F. BCTC and its Analogs;192 10.6;References;194 11;Chapter 6: Gating, Sensitization, and Desensitization of TRPV1;201 11.1;I. Overview;201 11.2;II. Introduction;202 11.3;III. Gating Properties of TRPV1;203 11.3.1;A. Capsaicin Action;203 11.3.2;B. Proton Action;205 11.3.3;C. Heat Activation;206 11.3.4;D. Voltage- and Time-Dependent Properties;206 11.3.5;E. Permeability;207 11.4;IV. Sensitization of TRPV1;2
07 11.4.1;A. Phosphorylation by PKA;207 11.4.2;B. Phosphorylation by PKC;208 11.4.3;C. Sensitization by Other Mechanisms;210 11.5;V. Desensitization of TRPV1;211 11.5.1;A. Physiological Significance of Desensitization;211 11.5.2;B. Calmodulin-Mediated Desensitization;212 11.5.3;C. Modulation by Lipids;213 11.6;VI. Conclusions;213 11.7;References;214 12;Chapter 7: TRP Channels as Thermosensors;219 12.1;I. Overview;220 12.2;II. Introduction;220 12.2.1;A. General Features of TRP Channels;221 12.3;III. TRPV1 is a Noxious Heat Sensor;222 12.3.1;A. Heat Responses in DRG Neurons;222 12.3.2;B. Chemical Activators of TRPV1;223 12.3.3;C. Structure-Function Studies on TRPV1;224 12.3.4;D. Biochemical Regulation;225 12.3.5;E. TRPV1 in Inflammation;226 12.3.6;F. Lessons from "Knockout" Mice;227 12.3.7;G. Effects of TRPV1 Antagonists;228 12.3.8;H. Regulation of TRPV1 Expression;229 12.3.9;I. TRPV1 Expression in Other Neuronal and Non-Neuronal Cells;229 12.4;IV. TRPV2;230 12.4.1;A. Expression Pattern;231 12.4.2;B. Other Activators of TRPV2;232 12.5;V. TRPV3 and TRPV4 act as Warm Receptors;232 12.5.1;A. TRPV3;233 12.5.2;B. TRPV4;235 12.5.3;C. The Roles of TRPV3 and TRPV4 in Warm Responses of Native Cells;240 12.6;VI. Cold Activated Ion Channels;242 12.6.1;A. TRPM8 is Activated by Cool Temperatures and Menthol;243 12.6.2;B. TRPA1 as a Noxious Cold Receptor;246 12.6.3;C. Cold Hyperalgesia;247 12.7;VII. TRP Channels as Invertebrate Thermosensors;248 12.8;VIII. Conclusions;249 12.9;References;249 13;Chapter 8: Acid Sensing Ionic Channels;261 13.1;I. Overview;262 13.2;II. Introduction;262 13.3;III. Native Proton-Gated Cation Channels in Sensory Neurons;263 13.4;IV. Cloned ASICs;265 13.5;V. Properties of Cloned ASICs;267 13.5.1;A. Homomeric ASICs;267 13.5.2;B. Heteromultimeric ASICs;271 13.5.3;C. Pharmacology of ASICs;273 13.5.4;D. Modulators of ASICs;275 13.6;VI. ASIC Transcripts, Protein, and Currents in Sensory Neurons;279 13.6.1;A. ASIC Transcripts;279 13.6.2;B. ASIC Immunoreactivity;
280 13.6.3;C. Native ASIC-Like Currents Characterized in Sensory Neurons;280 13.7;VII. Role of ASICs in Nociception;281 13.7.1;A. Do ASICs Meet the Requirements for an Acid Sensor in Pain Perception?;281 13.7.2;B. Evidence for a Role of ASICs in Acid-Induced Pain Perception and Hyperalgesia;283 13.7.3;C. ASICs and Mechanosensation;285 13.7.4;D. ASICs in Spinal Cord;287 13.8;VIII. Conclusions;287 13.8.1;A. ASICs and Mechanosensation;287 13.8.2;B. ASICs and Acid Sensing;288 13.8.3;C. Multiple Pathways for Acid and Mechanosensing Might Coexist;289 13.9;References;290 14;Chapter 9: P2X Receptors in Sensory Neurons;297 14.1;I. Overview;297 14.2;II. Introduction;298 14.3;III. Molecular Structure and Pharmacological Profiles of P2X Receptors;299 14.4;IV. Electrophysiological Responses Following the Activation of P2X Receptors in Sensory Neurons;301 14.5;V. Distribution of P2X Receptors in Sensory Neurons;304 14.6;VI. P2X Receptors at Central and Peripheral Terminals;306 14.7;VII. Activating P2X Receptors Causes and Modulates Pain Sensation;309 14.8;VIII. Persistent Peripheral Inflammation Enhances P2X.Receptor Expression and their Function, thereby Causing Pain;311 14.9;IX. P2X Receptors in Sensory Neurons Have Crucial Roles in Neuropathic Pain;314 14.10;X. P2X4 Receptors in Spinal Microglia are Essential for Neuropathic Pain;319 14.11;XI. Concluding Remarks;320 14.12;References;321 15;Chapter 10: Voltage-Gated Sodium Channels and Neuropathic Pain;331 15.1;I. Overview;331 15.2;II. Introduction;332 15.3;III. The Structure of VGSCs;333 15.4;IV. Subtypes of VGSCs and Sodium Currents in Sensory.Neurons;333 15.5;V. TTXs VGSCs are Important for Ectopic Discharges and Neuropathic Pain;335 15.6;VI. NAv1.3 VGSC May be the Critical Subtype for Ectopic Discharge Generation;335 15.7;VII. The Involvement of TTXr VGSCs in Neuropathic Pain;337 15.8;VIII. Conclusions;338 15.9;References;339 16;Chapter 11: Voltage-Gated Potassium Channels in Sensory Neurons;343 16.1;I. Overview;343 16.2;II
. Introduction;344 16.3;III. Nociceptor Excitability;346 16.4;IV. Basics of Kv Channels;346 16.5;V. Classes of Native Kv Currents;347 16.6;VI. Native Kv Channels in Nociceptive Neurons;349 16.7;VII. Changes in Kv Currents and Pain;353 16.8;VIII. Kv Channel Gene Expression in Sensory Neurons;355 16.9;IX. Analyses of Kv Channel Protein Expression in Nociceptive Neurons;357 16.10;X. Kv1 Channel Subunits and Subunit Combinations Define Distinct Populations of Sensory Neurons;360 16.11;XI. Kv Channel Localization in Sensory Neurons;363 16.12;XII. Kv Channels and Nerve Injury;364 16.13;XIII. Genetic Intervention in Kv Channel Expression;365 16.14;XIV. Conclusions;366 16.15;References;367 17;Chapter 12: Two-Pore Domain Potassium Channels in Sensory Transduction;373 17.1;I. Overview;373 17.2;II. Introduction;374 17.3;III. K2P Channel Family;375 17.3.1;A. General Properties;375 17.3.2;B. Properties of K2P Channel Subfamilies;375 17.3.3;C. Single Channel Properties of K2P Channels;379 17.4;IV. Expression of K2P Channels in Sensory Neurons;381 17.5;V. Functional Properties of K2P Channels;381 17.5.1;A. K2P Channels are Active Background K+ Channels;381 17.5.2;B. K2P Channels Exhibit Diverse Functional Properties;382 17.6;VI. Summary;393 17.7;References;393 18;Chapter 13: Finding Sensory Neuron Mechanotransduction Components;399 18.1;I. Overview;399 18.2;II. Introduction;400 18.3;III. Mechanical Nociceptors and Other Relevant Mechanoreceptors;400 18.4;IV. Physiology of Transduction;403 18.5;V. Molecular Identity of the Transducer;405 18.5.1;A. Caenorhabditis elegans;405 18.5.2;B. Drosophila melanogaster;409 18.6;VI. Identification of Molecules Required for Vertebrate Sensory Mechanotransduction;410 18.7;VII. Candidate Gene Approaches;411 18.8;VIII. Are There Vertebrate mec Genes Involved in Sensory Mechanotransduction?;411 18.9;IX. Are TRP Channels Candidates for the Sensory Neuron Mechanotransducer?;415 18.10;X. Expression Cloning;418 18.11;XI. Imaging Mechanotransduction with
Fluorescent Dyes;420 18.12;XII. Using DNA Microarrays to Find Transduction Components;420 18.13;XIII. Biochemical Approaches;424 18.14;XIV. Conclusions;426 18.15;References;426 19;Chapter 14: Functional Diversity of Voltage-Dependent Ca2+ Channels in Nociception: Recent Progress in Genetic Studies;435 19.1;I. Overview;435 19.2;II. Introduction;436 19.3;III. VDCC Family;437 19.3.1;A. L-Type Ca2+ Channels in Nociception;441 19.3.2;B. N-Type Ca2+ Channels;442 19.3.3;C. P/Q-Type Ca2+ Channels in Nociception;445 19.3.4;D. R-Type Ca2+ Channels in Antinociception;446 19.3.5;E. T-Type Ca2+ Channels;446 19.3.6;F. Auxiliary Subunits of Voltage-Dependent Ca2+ Channels;451 19.4;IV. Conclusions;452 19.5;References;453 20;Chapter 15: Expression Patterns and Histological Aspects of TRP Channels in Sensory Neurons;459 20.1;I. Overview;459 20.2;II. TRPV1 (VR1);460 20.2.1;A. TRPV1 and TrkA;462 20.2.2;B. TRPV1 and SP;463 20.2.3;C. TRPV1 and CGRP;463 20.2.4;D. TRPV1 and P2X Receptors;464 20.2.5;E. TRPV1 and CB1 Receptor;465 20.2.6;F. TRPV1 and PKC;465 20.2.7;G. TRPV1 and PKA;465 20.2.8;H. TRPV1 and Somatostatin Receptor (SSTRs);466 20.3;III. TRPV2 (VRL1);466 20.4;IV. TRPV3 (Also Known as VRL3);467 20.5;V. TRPV4 (Also Known as VRL-2/OTRPC4/VR-OAC/TRP12);467 20.6;VI. TRPM8 (Also Known as CMR1);468 20.7;VII. TRPA1 (Renamed from ANKTM1);468 20.8;VIII. Conclusions;469 20.9;References;470 21;Subject Index;477