Canning / Spina Sensory Nerves

1. Auflage 2009
ISBN: 978-3-540-79090-7
Verlag: Springer Berlin Heidelberg
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 194, 624 Seiten

Reihe: Handbook of Experimental Pharmacology

The intention of this book is to provide a comprehensive and contemporary review of the biology of sensory nerves. The book is unique, as it comprehensively covers the role of sensory nerves across many therapeutic areas.

Autoren/Hrsg.

Spina, Domenico

Canning, Brendan J.

Inhaltsverzeichnis

1;Preface;5
2;Contents;5
3;Contributors;5
4;Part I: Role of Sensory Nerves in Disease;13
4.1;Neuropathic Pain: A Clinical Perspective;14
4.1.1;1 Introduction and Definition of Neuropathic Pain;15
4.1.2;2 Classification;16
4.1.3;3 Signs and Symptoms of Neuropathic Pain;19
4.1.4;4 Pathophysiological Mechanisms and Drug Targets in Neuropathic Pain;19
4.1.4.1;4.1 Peripheral Sensitization of Primary Afferents in Animals;21
4.1.4.2;4.2 Peripheral Sensitization of Primary Afferents in Patients;25
4.1.4.3;4.3 Pharmacological Approaches That Modify Peripheral Sensitization of Primary Afferents;27
4.1.4.3.1;4.3.1 Sodium-Channel Blockers;27
4.1.4.3.2;4.3.2 Topically Applied Capsaicin;28
4.1.4.4;4.4 Central Sensitization in the Spinal Cord in Animals;28
4.1.4.5;4.5 Central Sensitization of the Spinal Cord in Patients;29
4.1.4.6;4.6 Pharmacological Approaches That Modify Central Sensitization in the Spinal Cord;30
4.1.4.6.1;4.6.1 Calcium-Channel Modulators;30
4.1.4.6.2;4.6.2 Tramadol and Opioid Analgesics;31
4.1.4.6.3;4.6.3 NMDA-Receptor Antagonists;31
4.1.4.6.4;4.6.4 Cannabinoids;32
4.1.4.7;4.7 Central Descending and Intraspinal Control Systems: Inhibition and Fascilitation in Animals and Patients;32
4.1.4.8;4.8 Pharmacological Approaches That Modify Descending Control Systems;33
4.1.5;5 Treatment Guidelines in Neuropathic Pain;33
4.1.6;6 The Future: Diagnostic Tools To Dissect Individual Mechanisms and To Tailor Individual Treatment;35
4.1.7;7 Conclusion;37
4.1.8;Acknowledgements;37
4.1.9;References;37
4.2;Visceral Pain: The Neurophysiological Mechanism;42
4.2.1;1 Introduction;43
4.2.2;2 Behavioral Studies for Visceral Pain in Laboratory Animals;44
4.2.2.1;2.1 Inflammatory Model;44
4.2.2.2;2.2 Neonatal Maternal-Separation-Induced Stress Model;45
4.2.2.3;2.3 Neonatal Noxious-Stimulus-Induced Visceral Hyperalgesia Model;47
4.2.3;3 Contribution of Sensory Afferents in Visceral Pain;49
4.2.3.1;3.1 Anatomical Distribution of Visceral Afferents;49
4.2.3.2;3.2 Response Characteristics of Visceral Afferents;49
4.2.3.2.1;3.2.1 Visceral Afferents in the Gastrointestinal Tract;50
4.2.3.2.2;3.2.2 Visceral Afferents in the Urinary Tract;52
4.2.3.2.3;3.2.3 Visceral Afferents in the Female Reproductive Organs;60
4.2.3.3;3.3 Sensitization and Cross-Sensitization of Visceral Afferents;61
4.2.3.4;3.4 Pharmacological Modulation of Visceral Afferents and Visceral Pain;64
4.2.3.4.1;3.4.1 kappa-Opioid Receptor;64
4.2.3.4.2;3.4.2 P2X Purine Receptors;65
4.2.3.4.3;3.4.3 5-HT3 and 5-HT4 Seretonin Receptors;65
4.2.3.4.4;3.4.4 N-Methyl-d-aspartate Receptor (NMDAr);67
4.2.3.4.5;3.4.5 Tachykinin Receptors: NK1, NK2, and NK3;68
4.2.3.4.6;3.4.6 Transient Receptor Potential Vanilloid 1;68
4.2.3.4.7;3.4.7 GABAB Receptor;69
4.2.4;4 Conclusion;70
4.2.5;Acknowledgements;71
4.2.6;References;71
4.3;Migraine;86
4.3.1;1 Introduction;87
4.3.2;2 A Subset of Sensory (Nocifensor) Neurons Exerts a Dual Afferent and Efferent Function and Mediates Neurogenic Inflammation;88
4.3.3;3 CGRP, Its Receptor, and Receptor Antagonists;90
4.3.4;4 CGRP Release and CGRP-Mediated Responses;91
4.3.5;5 Sensory Neurons and Migraine;92
4.3.6;6 CGRP Antagonists in Migraine;93
4.3.7;7 Conclusions;95
4.3.8;Acknowledgements;96
4.3.9;References;96
4.4;Afferent Nerve Regulation of Bladder Function in Health and Disease;101
4.4.1;1 Anatomy and Innervation of the Lower Urinary Tract;102
4.4.1.1;1.1 Afferent Nerves;103
4.4.1.2;1.2 Central Afferent Pathways;106
4.4.2;2 Histological and Chemical Properties of Afferent Nerves;108
4.4.3;3 Anatomy and Putative Sensory Functions of the Urothelium;111
4.4.4;4 Properties of Afferent Receptors in the Lower Urinary Tract;113
4.4.4.1;4.1 Sacral Afferents;113
4.4.4.2;4.2 Lumbar Afferents;116
4.4.5;5 Electrophysiological Properties of Afferent Neurons;117
4.4.5.1;5.1 Passive Membrane Properties and Action Potentials;117
4.4.5.2;5.2 Sodium Channels;118
4.4.5.3;5.3 Potassium Channels;118
4.4.5.4;5.4 Calcium Channels;119
4.4.5.5;5.5 Purinergic Channels;120
4.4.5.6;5.6 Transient Receptor Potential Channels;120
4.4.5.7;5.7 Acid-Sensing Ion Channels;121
4.4.6;6 Role of Afferent Neurons in the Normal Control of the Lower Urinary Tract;121
4.4.6.1;6.1 Sympathetic Storage Reflexes;123
4.4.6.2;6.2 Urethral Sphincter Storage Reflexes;123
4.4.6.3;6.3 Voiding Reflexes;124
4.4.7;7 Plasticity of Afferent Neurons Induced by Spinal Cord Injury;124
4.4.7.1;7.1 Emergence of a C-Fiber Afferent Micturition Reflex;124
4.4.7.2;7.2 Role of Neurotrophic Factors;128
4.4.7.3;7.3 Changes in Firing Properties of Bladder Afferent Neurons After Spinal Cord Injury;128
4.4.7.4;7.4 Plasticity in Sodium and Potassium Channels After Spinal Cord Injury;129
4.4.8;8 Afferent Nerves and Idiopathic Detrusor Overactivity;129
4.4.9;9 Afferent Nerves and Urethral Outlet Obstruction;130
4.4.10;10 Afferent Nerves and Cystitis;131
4.4.11;11 Afferent Nerves and Diabetes Mellitus;136
4.4.12;12 Afferent Nerves and Interorgan Cross-Sensitization;136
4.4.13;13 Perspectives;137
4.4.14;References;138
4.5;Sensory Nerves and Airway Irritability;149
4.5.1;1 Introduction;150
4.5.2;2 Airway and Lung Afferent Nerve Subtypes;150
4.5.2.1;2.1 Slowly Adapting Receptors;151
4.5.2.2;2.2 Rapidly Adapting Receptors;152
4.5.2.3;2.3 C-Fibers;154
4.5.2.4;2.4 Cough Receptors;157
4.5.3;3 Autonomic Reflexes;159
4.5.3.1;3.1 Parasympathetic Nerve Regulation of Airway and Vascular Smooth Muscle and Mucus Secretion;159
4.5.3.2;3.2 Reflex Regulation of Airway Sympathetic Nerves;161
4.5.3.3;3.3 The Axon Reflex;162
4.5.4;4 Respiratory Reflexes;163
4.5.4.1;4.1 Respiratory Pattern Changes and Respiratory Sensations;163
4.5.4.2;4.2 Cough;164
4.5.5;5 CNS Pharmacology and Central Interactions Between Airway Afferent Nerve Subtypes;166
4.5.6;6 Airway Sensory Nerves and Bronchial Hyperresponsiveness;168
4.5.6.1;6.1 Defining Characteristics of Bronchial Hyperresponsiveness;168
4.5.6.2;6.2 Bronchial Hyperresponsiveness and Sensory Nerves;169
4.5.6.3;6.3 TRPV1 and Bronchial Hyperresponsiveness;172
4.5.6.4;6.4 TRPV1 Antagonist and Knockout Studies;176
4.5.7;7 Conclusions;177
4.5.8;References;177
4.6;Regulation of Cardiac Afferent Excitability in Ischemia;194
4.6.1;1 Introduction;195
4.6.2;2 The Responses of Myocardial Reflex During Ischemia;196
4.6.3;3 Chemical Mediators in Activation of Cardiac Spinal Afferent;197
4.6.3.1;3.1 Protons;197
4.6.3.2;3.2 Bradykinin and BK2 Receptors;199
4.6.3.3;3.3 Platelets and Glycoprotein IIb-IIIa Receptors;200
4.6.3.4;3.4 5-Hydroxytryptamine and 5-HT3 Receptors;203
4.6.3.5;3.5 Histamine and H1 Receptors;207
4.6.3.6;3.6 Thromboxane A2 and Thromboxane A2/Prostaglandin H2 Receptors;211
4.6.3.7;3.7 Reactive Oxygen Species;213
4.6.3.8;3.8 Adenosine;217
4.6.4;4 Interactions Between Chemical Mediators;218
4.6.4.1;4.1 Prostaglandins and Bradykinin;218
4.6.4.2;4.2 Bradykinin and Histamine;220
4.6.4.3;4.3 Thromboxane A2 and Bradykinin;222
4.6.5;5 Summary;224
4.6.6;Acknowledgements;225
4.6.7;References;225
4.7;Roles of Gastro-oesophageal Afferents in the Mechanisms and Symptoms of Reflux Disease;235
4.7.1;1 Pathways and Subtypes of Gastro-oesophageal Afferents;237
4.7.1.1;1.1 Anatomy of Gastro-oesophageal Afferents;237
4.7.1.1.1;1.1.1 Vagal Afferents;237
4.7.1.1.2;1.1.2 Spinal Afferents;239
4.7.1.2;1.2 Functional Properties of Gastro-oesophageal Afferent Endings;240
4.7.1.2.1;1.2.1 Vagal Afferents;240
4.7.1.2.2;1.2.2 Spinal Afferents;241
4.7.2;2 Pharmacology of Gastro-oesophageal Afferents;242
4.7.2.1;2.1 Excitatory Receptors;242
4.7.2.2;2.2 Inhibitory Receptors;248
4.7.2.3;2.3 Mechanosensory Ion Channels;250
4.7.2.4;2.4 Inflammatory Pharmacology;250
4.7.3;3 Oesophageal Symptoms in Humans;251
4.7.3.1;3.1 Stimuli and Sensory Perception;251
4.7.3.2;3.2 Classification of Disease According to Symptoms;253
4.7.3.3;3.3 Pharmacological Studies of Oesophageal Pain in Humans;253
4.7.3.4;3.4 Sensory Involvement in Motor Dysfunction;254
4.7.4;4 Origins of Gastro-oesophageal Reflux Disease;254
4.7.4.1;4.1 Current Treatment Does Not Relate to Cause;254
4.7.4.2;4.2 Neural Pathways and Pharmacology of Reflux;255
4.7.5;5 Conclusions;257
4.7.6;Acknowledgement;257
4.7.7;References;257
5;Part II: Cell and Molecular Mechanisms Regulating Sensory Nerve Function;266
5.1;Transient Receptor Potential Channels on Sensory Nerves;267
5.1.1;1 Discovery of Transient Receptor Potential Vanilloid Subfamily, Member 1: A Ticket into the Somatosensory System;268
5.1.2;2 TRP Channels as Molecular Sensors;269
5.1.2.1;2.1 TRPV1;269
5.1.2.2;2.2 TRPV2;271
5.1.2.3;2.3 TRPV3;271
5.1.2.4;2.4 TRPV4;271
5.1.2.5;2.5 TRPA1;272
5.1.2.6;2.6 TRPM8;273
5.1.3;3 TRP Channels as Mediators of Pain;274
5.1.3.1;3.1 TRPV1;274
5.1.3.2;3.2 TRPV2;275
5.1.3.3;3.3 TRPV3;275
5.1.3.4;3.4 TRPV4;276
5.1.3.5;3.5 TRPA1;277
5.1.3.6;3.6 TRPM8;277
5.1.4;4 Pharmacology of TRP Channels;278
5.1.4.1;4.1 Nonselective TRP Channel Agonists and Antagonists;279
5.1.4.2;4.2 TRPV1;279
5.1.4.3;4.3 TRPA1;280
5.1.4.4;4.4 TRPV3, TRPV4, and TRPM8;281
5.1.5;5 Conclusions;281
5.1.6;References;282
5.2;Acid-Sensitive Ion Channels and Receptors;288
5.2.1;1 Acid Sensing by Sensory Neurons;289
5.2.1.1;1.1 Acid as a Noxious Stimulus;289
5.2.1.2;1.2 Proton-Gated Currents in Sensory Neurons;290
5.2.2;2 Acid Sensors on Sensory Neurons;292
5.2.2.1;2.1 Acid-Sensing Ion Channels;292
5.2.2.2;2.2 TRP Ion Channels;295
5.2.2.2.1;2.2.1 TRPV1;295
5.2.2.2.2;2.2.2 TRPV4;297
5.2.2.2.3;2.2.3 TRPC4 and TRPC5;297
5.2.2.2.4;2.2.4 TRPP2 (PKD2L1, Polycystic Kidney Disease Like Ion Channel);298
5.2.2.3;2.3 K2P Channels;298
5.2.2.4;2.4 Proton-Sensing GPCRs;301
5.2.2.5;2.5 Ionotropic Purinoceptors;301
5.2.2.6;2.6 Other Acid-Sensitive Ion Channels;303
5.2.3;3 Physiological and Pathophysiological Implications of Acid Sensors;304
5.2.3.1;3.1 Sour Taste;304
5.2.3.2;3.2 Acidosis in the Gastrointestinal Tract;306
5.2.3.2.1;3.2.1 Acidity and Acidosis in the Gastrointestinal Tract;306
5.2.3.2.2;3.2.2 Acid Sensing as a Feedback in the Control of Foregut Homeostasis;306
5.2.3.2.3;3.2.3 Acid as a Factor in Abdominal Pain;308
5.2.3.3;3.3 Acidosis in the Urogenital Tract;310
5.2.3.4;3.4 Acidosis in the Pulmonary System;311
5.2.3.5;3.5 Acidosis in the Skin;312
5.2.3.6;3.6 Acid Sensors in the Carotid Body;313
5.2.3.7;3.7 Acidosis Due To Myocardial Ischaemia;314
5.2.3.8;3.8 Acidosis in the Skeletal Muscle;315
5.2.3.9;3.9 Acidosis in the Skeleton;315
5.2.4;4 Pharmacological Interference with Acid Sensors;317
5.2.4.1;4.1 Acid-Sensing Ion Channels;317
5.2.4.2;4.2 TRPV Channels;319
5.2.4.3;4.3 K2P Channels;321
5.2.5;5 Conclusions;321
5.2.6;Acknowledgements;322
5.2.7;References;322
5.3;Purines and Sensory Nerves;338
5.3.1;1 Introduction;339
5.3.2;2 Peripheral Sensory Ganglionic Neurons;340
5.3.2.1;2.1 Dorsal Root Ganglia;341
5.3.2.2;2.2 Nodose Ganglia;343
5.3.2.3;2.3 Trigeminal Ganglia;344
5.3.2.4;2.4 Petrosal Ganglia;345
5.3.2.5;2.5 Retinal Ganglia;345
5.3.2.6;2.6 Intramural Enteric Sensory Neurons;346
5.3.3;3 Peripheral Sensory Nerve Terminals;348
5.3.3.1;3.1 Carotid Body;349
5.3.3.2;3.2 Lung;349
5.3.3.3;3.3 Gut;352
5.3.3.4;3.4 Urinary Bladder;353
5.3.3.5;3.5 Inner Ear;353
5.3.3.6;3.6 Eye;354
5.3.3.7;3.7 Nasal Organ;354
5.3.3.8;3.8 Taste Buds;355
5.3.3.9;3.9 Skin, Muscle and Joints;356
5.3.3.10;3.10 Heart;356
5.3.4;4 Central Sensory Nerves;356
5.3.4.1;4.1 Spinal Cord;357
5.3.4.2;4.2 Nucleus Tractus Solitarius;358
5.3.4.3;4.3 Ventrolateral Medulla;359
5.3.4.4;4.4 Sensory Nuclei;359
5.3.4.5;4.5 Trigeminal Mesencephalic Nucleus;360
5.3.4.6;4.6 Locus Coeruleus;360
5.3.4.7;4.7 Area Postrema;360
5.3.4.8;4.8 Hypothalamus;361
5.3.5;5 Purinergic Mechanosensory Transduction;362
5.3.5.1;5.1 Urinary Bladder;362
5.3.5.2;5.2 Ureter;364
5.3.5.3;5.3 Gut;365
5.3.5.4;5.4 Uterus;365
5.3.5.5;5.5 Tooth Pulp;365
5.3.5.6;5.6 Tongue;366
5.3.5.7;5.7 Skin and Joints;366
5.3.6;6 Purinergic Sensory Pathology;366
5.3.6.1;6.1 Pain;366
5.3.6.2;6.2 Migraine;371
5.3.6.3;6.3 Diseases of Special Senses;372
5.3.6.3.1;6.3.1 Eye;372
5.3.6.3.2;6.3.2 Ear;372
5.3.6.3.3;6.3.3 Nasal Organs;373
5.3.6.4;6.4 Bladder Diseases;373
5.3.6.5;6.5 Gut Disorders;374
5.3.6.6;6.6 Arthritis;375
5.3.6.7;6.7 Respiratory Diseases;376
5.3.6.8;6.8 Central Disorders;376
5.3.7;7 Development of Purinergic Sensory Signalling;376
5.3.8;8 Evolution of Purinergic Sensory Mechanisms;380
5.3.9;9 Concluding Comments;383
5.3.10;References;385
5.4;Sensory-Nerve-Derived Neuropeptides: Possible Therapeutic Targets;398
5.4.1;1 Introduction;399
5.4.2;2 Sensory-Nerve-Derived Neuropeptides;400
5.4.3;3 Substance P and the Tachykinin Family;401
5.4.3.1;3.1 An Inflammatory Role for Substance P in Arthritis;404
5.4.3.2;3.2 Substance P in Skin Diseases;404
5.4.3.3;3.3 Substance P and Sepsis;405
5.4.3.4;3.4 Substance P and the Gut;406
5.4.3.5;3.5 Clinical Trials with the Tachykinin Receptor Antagonists;406
5.4.4;4 Calcitonin Gene-Related Peptide;407
5.4.5;5 Galanin and Related Peptides;410
5.4.5.1;5.1 Galanin and Pain Processing;412
5.4.5.2;5.2 Galanin and the Gastrointestinal Tract;412
5.4.5.3;5.3 Vascular Effects of Galanin in the Cutaneous Microvasculature;413
5.4.6;6 Conclusions;414
5.4.7;Acknowledgement;414
5.4.8;References;414
5.5;Cytokine and Chemokine Regulation of Sensory Neuron Function;422
5.5.1;1 Introduction;423
5.5.2;2 Peripheral Nerve Injury and Inflammation;425
5.5.3;3 Early Events in Sensory Nerve Cytokine Signaling;427
5.5.4;4 Chemokines, Glia, and Chronic Pain;434
5.5.5;5 Downstream Cytokine Signaling;435
5.5.6;6 Chemokines and Their Receptors in Acute and Chronic Pain;436
5.5.7;7 Chemokine Interactions with Other Neurotransmitters;443
5.5.8;8 Conclusions;446
5.5.9;Acknowledgements;446
5.5.10;References;446
5.6;The Role of Peptides in Central Sensitization;455
5.6.1;1 Introduction;457
5.6.1.1;1.1 Concept of Central Sensitization;457
5.6.1.2;1.2 Phases of Central Sensitization;458
5.6.2;2 Contribution of Peptides to Central Sensitization;459
5.6.2.1;2.1 SP and CGRP as Prototypic Peptides in Central Sensitization;460
5.6.3;3 CGRP Receptors;461
5.6.3.1;3.1 Endogenous Ligands;461
5.6.3.2;3.2 Components of CGRP Receptors;461
5.6.3.3;3.3 Signal Transduction of CGRP Receptors;462
5.6.3.4;3.4 Distribution of CGRP Receptors within the Spinal Cord;462
5.6.3.5;3.5 Contribution of CGRP Receptors to the Induction of Central Sensitization;464
5.6.3.6;3.6 Contribution of CGRP Receptors to the Maintenance of Central Sensitization;465
5.6.4;4 Neurokinin Receptors;468
5.6.4.1;4.1 Endogenous Ligands;468
5.6.4.2;4.2 Neurokinin Receptor Subtypes;468
5.6.4.3;4.3 Signal Transduction of Neurokinin Receptors;469
5.6.4.4;4.4 Regulation of Neurokinin Receptors;470
5.6.4.5;4.5 Localization of Neurokinin Receptors in the Spinal Cord;472
5.6.4.5.1;4.5.1 NK1 Receptor;472
5.6.4.5.2;4.5.2 NK2 Receptor;473
5.6.4.5.3;4.5.3 NK3 Receptor;473
5.6.4.6;4.6 Contribution of Neurokinin Receptors to Development of Central Sensitization;474
5.6.4.6.1;4.6.1 NK1 Receptor;475
5.6.4.6.2;4.6.2 NK2 Receptor;478
5.6.4.6.3;4.6.3 NK3 Receptor;479
5.6.4.7;4.7 Neurokinin Receptors and Gene Expression;480
5.6.5;5 Summary;482
5.6.6;References;483
6;Part III: Current and Future Treatment Strategies Targeting Sensory Nerves;496
6.1;14: Opioids and Sensory Nerves;497
6.1.1;1 Introduction;498
6.1.2;2 Opioid Receptors;499
6.1.2.1;2.1 Opioid Receptor Types;499
6.1.2.2;2.2 Signal Transduction and Recycling;500
6.1.2.3;2.3 Opioid Receptors on Peripheral Sensory Neurons;501
6.1.2.4;2.4 Plasticity of Peripheral Opioid Receptors;502
6.1.2.4.1;2.4.1 Ontogeny;502
6.1.2.4.2;2.4.2 Influence of Inflammation;502
6.1.2.4.3;2.4.3 Influence of Nerve Damage;504
6.1.2.4.4;2.4.4 Sympathetic Neurons;504
6.1.3;3 Opioid Peptides;504
6.1.3.1;3.1 Opioid Peptides in Sensory Neurons;505
6.1.3.2;3.2 Opioid Peptides in Immune Cells;505
6.1.3.3;3.3 Migration of Opioid-Containing Cells to Inflamed Tissue;506
6.1.3.4;3.4 Release of Opioid Peptides from Immune Cells;506
6.1.4;4 Modulation of Pain and Inflammation;507
6.1.4.1;4.1 Exogenous Opioid Agonists;507
6.1.4.2;4.2 Exogenous Stimulation of Opioid Release from Inflammatory Cells;508
6.1.4.3;4.3 Endogenous Stimulation of Opioid Release from Inflammatory Cells;509
6.1.4.4;4.4 Opioid Tolerance;510
6.1.5;5 Clinical Implications and Perspectives;511
6.1.6;Acknowledgements;512
6.1.7;References;512
6.2;15: The Pharmacology of Voltage-Gated Sodium Channels in Sensory Neurones;521
6.2.1;1 Introduction;522
6.2.1.1;1.1 VGSC Structure;523
6.2.1.2;1.2 VGSC Function;524
6.2.2;2 Classification, Distribution and Proposed Function of VGSC a-Subunits in Peripheral Sensory Neurones;525
6.2.2.1;2.1 NaV1.1;526
6.2.2.2;2.2 NaV1.2;526
6.2.2.3;2.3 NaV1.3;526
6.2.2.4;2.4 NaV1.4;526
6.2.2.5;2.5 NaV1.5;526
6.2.2.6;2.6 NaV1.6;527
6.2.2.7;2.7 NaV1.7;527
6.2.2.8;2.8 NaV1.8 and NaV1.9;527
6.2.3;3 Modulation of VGSCs in Sensory Neurones by Receptor Signalling Systems;528
6.2.4;4 Drugs and Toxins Acting at VGSCs in Sensory Neurones;531
6.2.4.1;4.1 Local Anaesthetics;531
6.2.4.2;4.2 Antiarrhythmic Drugs;535
6.2.4.2.1;4.2.1 Class Ia;536
6.2.4.2.2;4.2.2 Class Ib;536
6.2.4.2.3;4.2.3 Class Ic;536
6.2.4.2.4;4.2.4 Mexiletine;537
6.2.4.2.5;4.2.5 Flecainide;537
6.2.4.3;4.3 Anticonvulsants;539
6.2.4.3.1;4.3.1 Anticonvulsants and Neuropathic Pain;540
6.2.4.3.2;4.3.2 Anticonvulsants and Persistent Sodium Current;541
6.2.4.4;4.4 Toxins and Related Drugs;541
6.2.4.4.1;4.4.1 ``Site 1´´ Toxins: TTX and Saxitoxin;542
6.2.4.4.2;4.4.2 ``Site 1´´ Toxins: mu-Conotoxins;544
6.2.4.4.3;4.4.3 ``Site 2´´ Toxins;545
6.2.4.4.4;4.4.4 ``Sites 3-9´´ Toxins and Drugs;547
6.2.4.5;4.5 Other Drugs;549
6.2.5;5 Conclusion;550
6.2.6;References;551
6.3;16: Role of Calcium in Regulating Primary Sensory Neuronal Excitability;564
6.3.1;1 Introduction;565
6.3.2;2 Morphology of Sensory Neurons;566
6.3.3;3 Biophysical and Pharmacological Properties of Voltage-Gated Calcium Channels;566
6.3.4;4 Calcium-Activated Currents;569
6.3.4.1;4.1 BK Channels;570
6.3.4.2;4.2 IK Channel;570
6.3.4.3;4.3 SK Channels;571
6.3.4.4;4.4 Other Ca2+-Activated Potassium Currents;573
6.3.4.5;4.5 Calcium-Dependent Chloride Currents;574
6.3.5;5 Extracellular Calcium Sensor;574
6.3.6;6 Calcium Regulation and Excitability;575
6.3.6.1;6.1 Plasma Membrane Calcium ATPase;576
6.3.6.2;6.2 Sodium-Calcium Exchanger;578
6.3.6.3;6.3 Ryanodine Receptors;578
6.3.6.4;6.4 Inositol Triphosphate Receptor;579
6.3.6.5;6.5 Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase;579
6.3.6.6;6.6 Mitochondria;580
6.3.7;7 Altered Excitability and Ca2+ Regulation as a Result of Peripheral Neuropathies;581
6.3.7.1;7.1 Chemotherapy-Induced Neuropathies;581
6.3.7.2;7.2 Diabetic-Induced Neuropathies;582
6.3.8;8 Nerve Injury;582
6.3.9;Acknowledgements;583
6.3.10;References;583
6.4;17: Future Treatment Strategies for Neuropathic Pain;589
6.4.1;1 Introduction;590
6.4.2;2 Future Treatment Strategies for NP;591
6.4.2.1;2.1 Voltage-Gated Ion Channel Blockers;591
6.4.2.2;2.2 Immune Cells and Their Released Factors in Neuropathic Pain;594
6.4.2.2.1;2.2.1 Periphery;595
6.4.2.2.2;2.2.2 Central;596
6.4.2.2.3;2.2.3 Which Factors Released from Immune Cells Modulate Pain Processing?;597
6.4.2.3;2.3 Protein Kinases;598
6.4.2.4;2.4 Gene Therapy;599
6.4.2.5;2.5 Neurotrophic Factors;601
6.4.2.5.1;2.5.1 NGF as a Peripheral Pain Mediator;601
6.4.2.5.2;2.5.2 BDNF as a Central Pain Mediator;603
6.4.2.6;2.6 Neuropeptides;605
6.4.2.7;2.7 Cannabinoids;605
6.4.2.8;2.8 Neurostimulation;606
6.4.3;3 Conclusions;607
6.4.4;References;608
7;: Index;616