Sensory Nerves (eBook)

Preface 5
Contents 5
Contributors 5
Part I: Role of Sensory Nerves in Disease 13
Neuropathic Pain: A Clinical Perspective 14
1 Introduction and Definition of Neuropathic Pain 15
2 Classification 16
3 Signs and Symptoms of Neuropathic Pain 19
4 Pathophysiological Mechanisms and Drug Targets in Neuropathic Pain 19
4.1 Peripheral Sensitization of Primary Afferents in Animals 21
4.2 Peripheral Sensitization of Primary Afferents in Patients 25
4.3 Pharmacological Approaches That Modify Peripheral Sensitization of Primary Afferents 27
4.3.1 Sodium-Channel Blockers 27
4.3.2 Topically Applied Capsaicin 28
4.4 Central Sensitization in the Spinal Cord in Animals 28
4.5 Central Sensitization of the Spinal Cord in Patients 29
4.6 Pharmacological Approaches That Modify Central Sensitization in the Spinal Cord 30
4.6.1 Calcium-Channel Modulators 30
4.6.2 Tramadol and Opioid Analgesics 31
4.6.3 NMDA-Receptor Antagonists 31
4.6.4 Cannabinoids 32
4.7 Central Descending and Intraspinal Control Systems: Inhibition and Fascilitation in Animals and Patients 32
4.8 Pharmacological Approaches That Modify Descending Control Systems 33
5 Treatment Guidelines in Neuropathic Pain 33
6 The Future: Diagnostic Tools To Dissect Individual Mechanisms and To Tailor Individual Treatment 35
7 Conclusion 37
Acknowledgements 37
References 37
Visceral Pain: The Neurophysiological Mechanism 42
1 Introduction 43
2 Behavioral Studies for Visceral Pain in Laboratory Animals 44
2.1 Inflammatory Model 44
2.2 Neonatal Maternal-Separation-Induced Stress Model 45
2.3 Neonatal Noxious-Stimulus-Induced Visceral Hyperalgesia Model 47
3 Contribution of Sensory Afferents in Visceral Pain 49
3.1 Anatomical Distribution of Visceral Afferents 49
3.2 Response Characteristics of Visceral Afferents 49
3.2.1 Visceral Afferents in the Gastrointestinal Tract 50
3.2.2 Visceral Afferents in the Urinary Tract 52
3.2.3 Visceral Afferents in the Female Reproductive Organs 60
3.3 Sensitization and Cross-Sensitization of Visceral Afferents 61
3.4 Pharmacological Modulation of Visceral Afferents and Visceral Pain 64
3.4.1 kappa-Opioid Receptor 64
3.4.2 P2X Purine Receptors 65
3.4.3 5-HT3 and 5-HT4 Seretonin Receptors 65
3.4.4 N-Methyl-d-aspartate Receptor (NMDAr) 67
3.4.5 Tachykinin Receptors: NK1, NK2, and NK3 68
3.4.6 Transient Receptor Potential Vanilloid 1 68
3.4.7 GABAB Receptor 69
4 Conclusion 70
Acknowledgements 71
References 71
Migraine 86
1 Introduction 87
2 A Subset of Sensory (Nocifensor) Neurons Exerts a Dual Afferent and Efferent Function and Mediates Neurogenic Inflammation 88
3 CGRP, Its Receptor, and Receptor Antagonists 90
4 CGRP Release and CGRP-Mediated Responses 91
5 Sensory Neurons and Migraine 92
6 CGRP Antagonists in Migraine 93
7 Conclusions 95
Acknowledgements 96
References 96
Afferent Nerve Regulation of Bladder Function in Health and Disease 101
1 Anatomy and Innervation of the Lower Urinary Tract 102
1.1 Afferent Nerves 103
1.2 Central Afferent Pathways 106
2 Histological and Chemical Properties of Afferent Nerves 108
3 Anatomy and Putative Sensory Functions of the Urothelium 111
4 Properties of Afferent Receptors in the Lower Urinary Tract 113
4.1 Sacral Afferents 113
4.2 Lumbar Afferents 116
5 Electrophysiological Properties of Afferent Neurons 117
5.1 Passive Membrane Properties and Action Potentials 117
5.2 Sodium Channels 118
5.3 Potassium Channels 118
5.4 Calcium Channels 119
5.5 Purinergic Channels 120
5.6 Transient Receptor Potential Channels 120
5.7 Acid-Sensing Ion Channels 121
6 Role of Afferent Neurons in the Normal Control of the Lower Urinary Tract 121
6.1 Sympathetic Storage Reflexes 123
6.2 Urethral Sphincter Storage Reflexes 123
6.3 Voiding Reflexes 124
7 Plasticity of Afferent Neurons Induced by Spinal Cord Injury 124
7.1 Emergence of a C-Fiber Afferent Micturition Reflex 124
7.2 Role of Neurotrophic Factors 128
7.3 Changes in Firing Properties of Bladder Afferent Neurons After Spinal Cord Injury 128
7.4 Plasticity in Sodium and Potassium Channels After Spinal Cord Injury 129
8 Afferent Nerves and Idiopathic Detrusor Overactivity 129
9 Afferent Nerves and Urethral Outlet Obstruction 130
10 Afferent Nerves and Cystitis 131
11 Afferent Nerves and Diabetes Mellitus 136
12 Afferent Nerves and Interorgan Cross-Sensitization 136
13 Perspectives 137
References 138
Sensory Nerves and Airway Irritability 149
1 Introduction 150
2 Airway and Lung Afferent Nerve Subtypes 150
2.1 Slowly Adapting Receptors 151
2.2 Rapidly Adapting Receptors 152
2.3 C-Fibers 154
2.4 Cough Receptors 157
3 Autonomic Reflexes 159
3.1 Parasympathetic Nerve Regulation of Airway and Vascular Smooth Muscle and Mucus Secretion 159
3.2 Reflex Regulation of Airway Sympathetic Nerves 161
3.3 The Axon Reflex 162
4 Respiratory Reflexes 163
4.1 Respiratory Pattern Changes and Respiratory Sensations 163
4.2 Cough 164
5 CNS Pharmacology and Central Interactions Between Airway Afferent Nerve Subtypes 166
6 Airway Sensory Nerves and Bronchial Hyperresponsiveness 168
6.1 Defining Characteristics of Bronchial Hyperresponsiveness 168
6.2 Bronchial Hyperresponsiveness and Sensory Nerves 169
6.3 TRPV1 and Bronchial Hyperresponsiveness 172
6.4 TRPV1 Antagonist and Knockout Studies 176
7 Conclusions 177
References 177
Regulation of Cardiac Afferent Excitability in Ischemia 194
1 Introduction 195
2 The Responses of Myocardial Reflex During Ischemia 196
3 Chemical Mediators in Activation of Cardiac Spinal Afferent 197
3.1 Protons 197
3.2 Bradykinin and BK2 Receptors 199
3.3 Platelets and Glycoprotein IIb-IIIa Receptors 200
3.4 5-Hydroxytryptamine and 5-HT3 Receptors 203
3.5 Histamine and H1 Receptors 207
3.6 Thromboxane A2 and Thromboxane A2/Prostaglandin H2 Receptors 211
3.7 Reactive Oxygen Species 213
3.8 Adenosine 217
4 Interactions Between Chemical Mediators 218
4.1 Prostaglandins and Bradykinin 218
4.2 Bradykinin and Histamine 220
4.3 Thromboxane A2 and Bradykinin 222
5 Summary 224
Acknowledgements 225
References 225
Roles of Gastro-oesophageal Afferents in the Mechanisms and Symptoms of Reflux Disease 235
1 Pathways and Subtypes of Gastro-oesophageal Afferents 237
1.1 Anatomy of Gastro-oesophageal Afferents 237
1.1.1 Vagal Afferents 237
1.1.2 Spinal Afferents 239
1.2 Functional Properties of Gastro-oesophageal Afferent Endings 240
1.2.1 Vagal Afferents 240
1.2.2 Spinal Afferents 241
2 Pharmacology of Gastro-oesophageal Afferents 242
2.1 Excitatory Receptors 242
2.2 Inhibitory Receptors 248
2.3 Mechanosensory Ion Channels 250
2.4 Inflammatory Pharmacology 250
3 Oesophageal Symptoms in Humans 251
3.1 Stimuli and Sensory Perception 251
3.2 Classification of Disease According to Symptoms 253
3.3 Pharmacological Studies of Oesophageal Pain in Humans 253
3.4 Sensory Involvement in Motor Dysfunction 254
4 Origins of Gastro-oesophageal Reflux Disease 254
4.1 Current Treatment Does Not Relate to Cause 254
4.2 Neural Pathways and Pharmacology of Reflux 255
5 Conclusions 257
Acknowledgement 257
References 257
Part II: Cell and Molecular Mechanisms Regulating Sensory Nerve Function 266
Transient Receptor Potential Channels on Sensory Nerves 267
1 Discovery of Transient Receptor Potential Vanilloid Subfamily, Member 1: A Ticket into the Somatosensory System 268
2 TRP Channels as Molecular Sensors 269
2.1 TRPV1 269
2.2 TRPV2 271
2.3 TRPV3 271
2.4 TRPV4 271
2.5 TRPA1 272
2.6 TRPM8 273
3 TRP Channels as Mediators of Pain 274
3.1 TRPV1 274
3.2 TRPV2 275
3.3 TRPV3 275
3.4 TRPV4 276
3.5 TRPA1 277
3.6 TRPM8 277
4 Pharmacology of TRP Channels 278
4.1 Nonselective TRP Channel Agonists and Antagonists 279
4.2 TRPV1 279
4.3 TRPA1 280
4.4 TRPV3, TRPV4, and TRPM8 281
5 Conclusions 281
References 282
Acid-Sensitive Ion Channels and Receptors 288
1 Acid Sensing by Sensory Neurons 289
1.1 Acid as a Noxious Stimulus 289
1.2 Proton-Gated Currents in Sensory Neurons 290
2 Acid Sensors on Sensory Neurons 292
2.1 Acid-Sensing Ion Channels 292
2.2 TRP Ion Channels 295
2.2.1 TRPV1 295
2.2.2 TRPV4 297
2.2.3 TRPC4 and TRPC5 297
2.2.4 TRPP2 (PKD2L1, Polycystic Kidney Disease Like Ion Channel) 298
2.3 K2P Channels 298
2.4 Proton-Sensing GPCRs 301
2.5 Ionotropic Purinoceptors 301
2.6 Other Acid-Sensitive Ion Channels 303
3 Physiological and Pathophysiological Implications of Acid Sensors 304
3.1 Sour Taste 304
3.2 Acidosis in the Gastrointestinal Tract 306
3.2.1 Acidity and Acidosis in the Gastrointestinal Tract 306
3.2.2 Acid Sensing as a Feedback in the Control of Foregut Homeostasis 306
3.2.3 Acid as a Factor in Abdominal Pain 308
3.3 Acidosis in the Urogenital Tract 310
3.4 Acidosis in the Pulmonary System 311
3.5 Acidosis in the Skin 312
3.6 Acid Sensors in the Carotid Body 313
3.7 Acidosis Due To Myocardial Ischaemia 314
3.8 Acidosis in the Skeletal Muscle 315
3.9 Acidosis in the Skeleton 315
4 Pharmacological Interference with Acid Sensors 317
4.1 Acid-Sensing Ion Channels 317
4.2 TRPV Channels 319
4.3 K2P Channels 321
5 Conclusions 321
Acknowledgements 322
References 322
Purines and Sensory Nerves 338
1 Introduction 339
2 Peripheral Sensory Ganglionic Neurons 340
2.1 Dorsal Root Ganglia 341
2.2 Nodose Ganglia 343
2.3 Trigeminal Ganglia 344
2.4 Petrosal Ganglia 345
2.5 Retinal Ganglia 345
2.6 Intramural Enteric Sensory Neurons 346
3 Peripheral Sensory Nerve Terminals 348
3.1 Carotid Body 349
3.2 Lung 349
3.3 Gut 352
3.4 Urinary Bladder 353
3.5 Inner Ear 353
3.6 Eye 354
3.7 Nasal Organ 354
3.8 Taste Buds 355
3.9 Skin, Muscle and Joints 356
3.10 Heart 356
4 Central Sensory Nerves 356
4.1 Spinal Cord 357
4.2 Nucleus Tractus Solitarius 358
4.3 Ventrolateral Medulla 359
4.4 Sensory Nuclei 359
4.5 Trigeminal Mesencephalic Nucleus 360
4.6 Locus Coeruleus 360
4.7 Area Postrema 360
4.8 Hypothalamus 361
5 Purinergic Mechanosensory Transduction 362
5.1 Urinary Bladder 362
5.2 Ureter 364
5.3 Gut 365
5.4 Uterus 365
5.5 Tooth Pulp 365
5.6 Tongue 366
5.7 Skin and Joints 366
6 Purinergic Sensory Pathology 366
6.1 Pain 366
6.2 Migraine 371
6.3 Diseases of Special Senses 372
6.3.1 Eye 372
6.3.2 Ear 372
6.3.3 Nasal Organs 373
6.4 Bladder Diseases 373
6.5 Gut Disorders 374
6.6 Arthritis 375
6.7 Respiratory Diseases 376
6.8 Central Disorders 376
7 Development of Purinergic Sensory Signalling 376
8 Evolution of Purinergic Sensory Mechanisms 380
9 Concluding Comments 383
References 385
Sensory-Nerve-Derived Neuropeptides: Possible Therapeutic Targets 398
1 Introduction 399
2 Sensory-Nerve-Derived Neuropeptides 400
3 Substance P and the Tachykinin Family 401
3.1 An Inflammatory Role for Substance P in Arthritis 404
3.2 Substance P in Skin Diseases 404
3.3 Substance P and Sepsis 405
3.4 Substance P and the Gut 406
3.5 Clinical Trials with the Tachykinin Receptor Antagonists 406
4 Calcitonin Gene-Related Peptide 407
5 Galanin and Related Peptides 410
5.1 Galanin and Pain Processing 412
5.2 Galanin and the Gastrointestinal Tract 412
5.3 Vascular Effects of Galanin in the Cutaneous Microvasculature 413
6 Conclusions 414
Acknowledgement 414
References 414
Cytokine and Chemokine Regulation of Sensory Neuron Function 422
1 Introduction 423
2 Peripheral Nerve Injury and Inflammation 425
3 Early Events in Sensory Nerve Cytokine Signaling 427
4 Chemokines, Glia, and Chronic Pain 434
5 Downstream Cytokine Signaling 435
6 Chemokines and Their Receptors in Acute and Chronic Pain 436
7 Chemokine Interactions with Other Neurotransmitters 443
8 Conclusions 446
Acknowledgements 446
References 446
The Role of Peptides in Central Sensitization 455
1 Introduction 457
1.1 Concept of Central Sensitization 457
1.2 Phases of Central Sensitization 458
2 Contribution of Peptides to Central Sensitization 459
2.1 SP and CGRP as Prototypic Peptides in Central Sensitization 460
3 CGRP Receptors 461
3.1 Endogenous Ligands 461
3.2 Components of CGRP Receptors 461
3.3 Signal Transduction of CGRP Receptors 462
3.4 Distribution of CGRP Receptors within the Spinal Cord 462
3.5 Contribution of CGRP Receptors to the Induction of Central Sensitization 464
3.6 Contribution of CGRP Receptors to the Maintenance of Central Sensitization 465
4 Neurokinin Receptors 468
4.1 Endogenous Ligands 468
4.2 Neurokinin Receptor Subtypes 468
4.3 Signal Transduction of Neurokinin Receptors 469
4.4 Regulation of Neurokinin Receptors 470
4.5 Localization of Neurokinin Receptors in the Spinal Cord 472
4.5.1 NK1 Receptor 472
4.5.2 NK2 Receptor 473
4.5.3 NK3 Receptor 473
4.6 Contribution of Neurokinin Receptors to Development of Central Sensitization 474
4.6.1 NK1 Receptor 475
4.6.2 NK2 Receptor 478
4.6.3 NK3 Receptor 479
4.7 Neurokinin Receptors and Gene Expression 480
5 Summary 482
References 483
Part III: Current and Future Treatment Strategies Targeting Sensory Nerves 496
14: Opioids and Sensory Nerves 497
1 Introduction 498
2 Opioid Receptors 499
2.1 Opioid Receptor Types 499
2.2 Signal Transduction and Recycling 500
2.3 Opioid Receptors on Peripheral Sensory Neurons 501
2.4 Plasticity of Peripheral Opioid Receptors 502
2.4.1 Ontogeny 502
2.4.2 Influence of Inflammation 502
2.4.3 Influence of Nerve Damage 504
2.4.4 Sympathetic Neurons 504
3 Opioid Peptides 504
3.1 Opioid Peptides in Sensory Neurons 505
3.2 Opioid Peptides in Immune Cells 505
3.3 Migration of Opioid-Containing Cells to Inflamed Tissue 506
3.4 Release of Opioid Peptides from Immune Cells 506
4 Modulation of Pain and Inflammation 507
4.1 Exogenous Opioid Agonists 507
4.2 Exogenous Stimulation of Opioid Release from Inflammatory Cells 508
4.3 Endogenous Stimulation of Opioid Release from Inflammatory Cells 509
4.4 Opioid Tolerance 510
5 Clinical Implications and Perspectives 511
Acknowledgements 512
References 512
15: The Pharmacology of Voltage-Gated Sodium Channels in Sensory Neurones 521
1 Introduction 522
1.1 VGSC Structure 523
1.2 VGSC Function 524
2 Classification, Distribution and Proposed Function of VGSC a-Subunits in Peripheral Sensory Neurones 525
2.1 NaV1.1 526
2.2 NaV1.2 526
2.3 NaV1.3 526
2.4 NaV1.4 526
2.5 NaV1.5 526
2.6 NaV1.6 527
2.7 NaV1.7 527
2.8 NaV1.8 and NaV1.9 527
3 Modulation of VGSCs in Sensory Neurones by Receptor Signalling Systems 528
4 Drugs and Toxins Acting at VGSCs in Sensory Neurones 531
4.1 Local Anaesthetics 531
4.2 Antiarrhythmic Drugs 535
4.2.1 Class Ia 536
4.2.2 Class Ib 536
4.2.3 Class Ic 536
4.2.4 Mexiletine 537
4.2.5 Flecainide 537
4.3 Anticonvulsants 539
4.3.1 Anticonvulsants and Neuropathic Pain 540
4.3.2 Anticonvulsants and Persistent Sodium Current 541
4.4 Toxins and Related Drugs 541
4.4.1 ``Site 1´´ Toxins: TTX and Saxitoxin 542
4.4.2 ``Site 1´´ Toxins: mu-Conotoxins 544
4.4.3 ``Site 2´´ Toxins 545
4.4.4 ``Sites 3-9´´ Toxins and Drugs 547
4.5 Other Drugs 549
5 Conclusion 550
References 551
16: Role of Calcium in Regulating Primary Sensory Neuronal Excitability 564
1 Introduction 565
2 Morphology of Sensory Neurons 566
3 Biophysical and Pharmacological Properties of Voltage-Gated Calcium Channels 566
4 Calcium-Activated Currents 569
4.1 BK Channels 570
4.2 IK Channel 570
4.3 SK Channels 571
4.4 Other Ca2+-Activated Potassium Currents 573
4.5 Calcium-Dependent Chloride Currents 574
5 Extracellular Calcium Sensor 574
6 Calcium Regulation and Excitability 575
6.1 Plasma Membrane Calcium ATPase 576
6.2 Sodium-Calcium Exchanger 578
6.3 Ryanodine Receptors 578
6.4 Inositol Triphosphate Receptor 579
6.5 Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 579
6.6 Mitochondria 580
7 Altered Excitability and Ca2+ Regulation as a Result of Peripheral Neuropathies 581
7.1 Chemotherapy-Induced Neuropathies 581
7.2 Diabetic-Induced Neuropathies 582
8 Nerve Injury 582
Acknowledgements 583
References 583
17: Future Treatment Strategies for Neuropathic Pain 589
1 Introduction 590
2 Future Treatment Strategies for NP 591
2.1 Voltage-Gated Ion Channel Blockers 591
2.2 Immune Cells and Their Released Factors in Neuropathic Pain 594
2.2.1 Periphery 595
2.2.2 Central 596
2.2.3 Which Factors Released from Immune Cells Modulate Pain Processing? 597
2.3 Protein Kinases 598
2.4 Gene Therapy 599
2.5 Neurotrophic Factors 601
2.5.1 NGF as a Peripheral Pain Mediator 601
2.5.2 BDNF as a Central Pain Mediator 603
2.6 Neuropeptides 605
2.7 Cannabinoids 605
2.8 Neurostimulation 606
3 Conclusions 607
References 608
: Index 616