Handbook of Experimental Pharmacology, Vol. 194: Sensory Nerves

front-matter.pdf......Page 2
Neuropathic Pain: A Clinical Perspective......Page 13
1 Introduction and Definition of Neuropathic Pain......Page 14
2 Classification......Page 15
4 Pathophysiological Mechanisms and Drug Targets in Neuropathic Pain......Page 18
4.1 Peripheral Sensitization of Primary Afferents in Animals......Page 20
4.2 Peripheral Sensitization of Primary Afferents in Patients......Page 24
4.3.1 Sodium-Channel Blockers......Page 26
4.4 Central Sensitization in the Spinal Cord in Animals......Page 27
4.5 Central Sensitization of the Spinal Cord in Patients......Page 28
4.6.1 Calcium-Channel Modulators......Page 29
4.6.3 NMDA-Receptor Antagonists......Page 30
4.7 Central Descending and Intraspinal Control Systems: Inhibition and Fascilitation in Animals and Patients......Page 31
5 Treatment Guidelines in Neuropathic Pain......Page 32
6 The Future: Diagnostic Tools To Dissect Individual Mechanisms and To Tailor Individual Treatment......Page 34
References......Page 36
Visceral Pain: The Neurophysiological Mechanism......Page 41
1 Introduction......Page 42
2.1 Inflammatory Model......Page 43
2.2 Neonatal Maternal-Separation-Induced Stress Model......Page 44
2.3 Neonatal Noxious-Stimulus-Induced Visceral Hyperalgesia Model......Page 46
3.2 Response Characteristics of Visceral Afferents......Page 48
3.2.1 Visceral Afferents in the Gastrointestinal Tract......Page 49
3.2.2 Visceral Afferents in the Urinary Tract......Page 51
3.2.3 Visceral Afferents in the Female Reproductive Organs......Page 59
3.3 Sensitization and Cross-Sensitization of Visceral Afferents......Page 60
3.4.1 kappa-Opioid Receptor......Page 63
3.4.3 5-HT3 and 5-HT4 Seretonin Receptors......Page 64
3.4.4 N-Methyl-d-aspartate Receptor (NMDAr)......Page 66
3.4.6 Transient Receptor Potential Vanilloid 1......Page 67
3.4.7 GABAB Receptor......Page 68
4 Conclusion......Page 69
References......Page 70
Migraine......Page 85
1 Introduction......Page 86
2 A Subset of Sensory (Nocifensor) Neurons Exerts a Dual Afferent and Efferent Function and Mediates Neurogenic Inflammation......Page 87
3 CGRP, Its Receptor, and Receptor Antagonists......Page 89
4 CGRP Release and CGRP-Mediated Responses......Page 90
5 Sensory Neurons and Migraine......Page 91
6 CGRP Antagonists in Migraine......Page 92
7 Conclusions......Page 94
References......Page 95
Afferent Nerve Regulation of Bladder Function in Health and Disease......Page 100
1 Anatomy and Innervation of the Lower Urinary Tract......Page 101
1.1 Afferent Nerves......Page 102
1.2 Central Afferent Pathways......Page 105
2 Histological and Chemical Properties of Afferent Nerves......Page 107
3 Anatomy and Putative Sensory Functions of the Urothelium......Page 110
4.1 Sacral Afferents......Page 112
4.2 Lumbar Afferents......Page 115
5.1 Passive Membrane Properties and Action Potentials......Page 116
5.3 Potassium Channels......Page 117
5.4 Calcium Channels......Page 118
5.6 Transient Receptor Potential Channels......Page 119
6 Role of Afferent Neurons in the Normal Control of the Lower Urinary Tract......Page 120
6.2 Urethral Sphincter Storage Reflexes......Page 122
7.1 Emergence of a C-Fiber Afferent Micturition Reflex......Page 123
7.3 Changes in Firing Properties of Bladder Afferent Neurons After Spinal Cord Injury......Page 127
8 Afferent Nerves and Idiopathic Detrusor Overactivity......Page 128
9 Afferent Nerves and Urethral Outlet Obstruction......Page 129
10 Afferent Nerves and Cystitis......Page 130
12 Afferent Nerves and Interorgan Cross-Sensitization......Page 135
13 Perspectives......Page 136
References......Page 137
Sensory Nerves and Airway Irritability......Page 148
2 Airway and Lung Afferent Nerve Subtypes......Page 149
2.1 Slowly Adapting Receptors......Page 150
2.2 Rapidly Adapting Receptors......Page 151
2.3 C-Fibers......Page 153
2.4 Cough Receptors......Page 156
3.1 Parasympathetic Nerve Regulation of Airway and Vascular Smooth Muscle and Mucus Secretion......Page 158
3.2 Reflex Regulation of Airway Sympathetic Nerves......Page 160
3.3 The Axon Reflex......Page 161
4.1 Respiratory Pattern Changes and Respiratory Sensations......Page 162
4.2 Cough......Page 163
5 CNS Pharmacology and Central Interactions Between Airway Afferent Nerve Subtypes......Page 165
6.1 Defining Characteristics of Bronchial Hyperresponsiveness......Page 167
6.2 Bronchial Hyperresponsiveness and Sensory Nerves......Page 168
6.3 TRPV1 and Bronchial Hyperresponsiveness......Page 171
6.4 TRPV1 Antagonist and Knockout Studies......Page 175
References......Page 176
Regulation of Cardiac Afferent Excitability in Ischemia......Page 193
1 Introduction......Page 194
2 The Responses of Myocardial Reflex During Ischemia......Page 195
3.1 Protons......Page 196
3.2 Bradykinin and BK2 Receptors......Page 198
3.3 Platelets and Glycoprotein IIb-IIIa Receptors......Page 199
3.4 5-Hydroxytryptamine and 5-HT3 Receptors......Page 202
3.5 Histamine and H1 Receptors......Page 206
3.6 Thromboxane A2 and Thromboxane A2/Prostaglandin H2 Receptors......Page 210
3.7 Reactive Oxygen Species......Page 212
3.8 Adenosine......Page 216
4.1 Prostaglandins and Bradykinin......Page 217
4.2 Bradykinin and Histamine......Page 219
4.3 Thromboxane A2 and Bradykinin......Page 221
5 Summary......Page 223
References......Page 224
Roles of Gastro-oesophageal Afferents in the Mechanisms and Symptoms of Reflux Disease......Page 234
1.1.1 Vagal Afferents......Page 236
1.1.2 Spinal Afferents......Page 238
1.2.1 Vagal Afferents......Page 239
1.2.2 Spinal Afferents......Page 240
2.1 Excitatory Receptors......Page 241
2.2 Inhibitory Receptors......Page 247
2.4 Inflammatory Pharmacology......Page 249
3.1 Stimuli and Sensory Perception......Page 250
3.3 Pharmacological Studies of Oesophageal Pain in Humans......Page 252
4.1 Current Treatment Does Not Relate to Cause......Page 253
4.2 Neural Pathways and Pharmacology of Reflux......Page 254
References......Page 256
Transient Receptor Potential Channels on Sensory Nerves......Page 265
1 Discovery of Transient Receptor Potential Vanilloid Subfamily, Member 1: A Ticket into the Somatosensory System......Page 266
2.1 TRPV1......Page 267
2.4 TRPV4......Page 269
2.5 TRPA1......Page 270
2.6 TRPM8......Page 271
3.1 TRPV1......Page 272
3.3 TRPV3......Page 273
3.4 TRPV4......Page 274
3.6 TRPM8......Page 275
4 Pharmacology of TRP Channels......Page 276
4.2 TRPV1......Page 277
4.3 TRPA1......Page 278
5 Conclusions......Page 279
References......Page 280
Acid-Sensitive Ion Channels and Receptors......Page 286
1.1 Acid as a Noxious Stimulus......Page 287
1.2 Proton-Gated Currents in Sensory Neurons......Page 288
2.1 Acid-Sensing Ion Channels......Page 290
2.2.1 TRPV1......Page 293
2.2.3 TRPC4 and TRPC5......Page 295
2.3 K2P Channels......Page 296
2.5 Ionotropic Purinoceptors......Page 299
2.6 Other Acid-Sensitive Ion Channels......Page 301
3.1 Sour Taste......Page 302
3.2.2 Acid Sensing as a Feedback in the Control of Foregut Homeostasis......Page 304
3.2.3 Acid as a Factor in Abdominal Pain......Page 306
3.3 Acidosis in the Urogenital Tract......Page 308
3.4 Acidosis in the Pulmonary System......Page 309
3.5 Acidosis in the Skin......Page 310
3.6 Acid Sensors in the Carotid Body......Page 311
3.7 Acidosis Due To Myocardial Ischaemia......Page 312
3.9 Acidosis in the Skeleton......Page 313
4.1 Acid-Sensing Ion Channels......Page 315
4.2 TRPV Channels......Page 317
5 Conclusions......Page 319
References......Page 320
Purines and Sensory Nerves......Page 336
1 Introduction......Page 337
2 Peripheral Sensory Ganglionic Neurons......Page 338
2.1 Dorsal Root Ganglia......Page 339
2.2 Nodose Ganglia......Page 341
2.3 Trigeminal Ganglia......Page 342
2.5 Retinal Ganglia......Page 343
2.6 Intramural Enteric Sensory Neurons......Page 344
3 Peripheral Sensory Nerve Terminals......Page 346
3.2 Lung......Page 347
3.3 Gut......Page 350
3.5 Inner Ear......Page 351
3.7 Nasal Organ......Page 352
3.8 Taste Buds......Page 353
4 Central Sensory Nerves......Page 354
4.1 Spinal Cord......Page 355
4.2 Nucleus Tractus Solitarius......Page 356
4.4 Sensory Nuclei......Page 357
4.7 Area Postrema......Page 358
4.8 Hypothalamus......Page 359
5.1 Urinary Bladder......Page 360
5.2 Ureter......Page 362
5.5 Tooth Pulp......Page 363
6.1 Pain......Page 364
6.2 Migraine......Page 369
6.3.2 Ear......Page 370
6.4 Bladder Diseases......Page 371
6.5 Gut Disorders......Page 372
6.6 Arthritis......Page 373
7 Development of Purinergic Sensory Signalling......Page 374
8 Evolution of Purinergic Sensory Mechanisms......Page 378
9 Concluding Comments......Page 381
References......Page 383
Sensory-Nerve-Derived Neuropeptides: Possible Therapeutic Targets......Page 396
1 Introduction......Page 397
2 Sensory-Nerve-Derived Neuropeptides......Page 398
3 Substance P and the Tachykinin Family......Page 399
3.2 Substance P in Skin Diseases......Page 402
3.3 Substance P and Sepsis......Page 403
3.5 Clinical Trials with the Tachykinin Receptor Antagonists......Page 404
4 Calcitonin Gene-Related Peptide......Page 405
5 Galanin and Related Peptides......Page 408
5.2 Galanin and the Gastrointestinal Tract......Page 410
5.3 Vascular Effects of Galanin in the Cutaneous Microvasculature......Page 411
References......Page 412
Cytokine and Chemokine Regulation of Sensory Neuron Function......Page 420
1 Introduction......Page 421
2 Peripheral Nerve Injury and Inflammation......Page 423
3 Early Events in Sensory Nerve Cytokine Signaling......Page 425
4 Chemokines, Glia, and Chronic Pain......Page 432
5 Downstream Cytokine Signaling......Page 433
6 Chemokines and Their Receptors in Acute and Chronic Pain......Page 434
7 Chemokine Interactions with Other Neurotransmitters......Page 441
References......Page 444
The Role of Peptides in Central Sensitization......Page 453
1.1 Concept of Central Sensitization......Page 455
1.2 Phases of Central Sensitization......Page 456
2 Contribution of Peptides to Central Sensitization......Page 457
2.1 SP and CGRP as Prototypic Peptides in Central Sensitization......Page 458
3.2 Components of CGRP Receptors......Page 459
3.4 Distribution of CGRP Receptors within the Spinal Cord......Page 460
3.5 Contribution of CGRP Receptors to the Induction of Central Sensitization......Page 462
3.6 Contribution of CGRP Receptors to the Maintenance of Central Sensitization......Page 463
4.2 Neurokinin Receptor Subtypes......Page 466
4.3 Signal Transduction of Neurokinin Receptors......Page 467
4.4 Regulation of Neurokinin Receptors......Page 468
4.5.1 NK1 Receptor......Page 470
4.5.3 NK3 Receptor......Page 471
4.6 Contribution of Neurokinin Receptors to Development of Central Sensitization......Page 472
4.6.1 NK1 Receptor......Page 473
4.6.2 NK2 Receptor......Page 476
4.6.3 NK3 Receptor......Page 477
4.7 Neurokinin Receptors and Gene Expression......Page 478
5 Summary......Page 480
References......Page 481
14: Opioids and Sensory Nerves......Page 494
1 Introduction......Page 495
2.1 Opioid Receptor Types......Page 496
2.2 Signal Transduction and Recycling......Page 497
2.3 Opioid Receptors on Peripheral Sensory Neurons......Page 498
2.4.2 Influence of Inflammation......Page 499
3 Opioid Peptides......Page 501
3.2 Opioid Peptides in Immune Cells......Page 502
3.4 Release of Opioid Peptides from Immune Cells......Page 503
4.1 Exogenous Opioid Agonists......Page 504
4.2 Exogenous Stimulation of Opioid Release from Inflammatory Cells......Page 505
4.3 Endogenous Stimulation of Opioid Release from Inflammatory Cells......Page 506
4.4 Opioid Tolerance......Page 507
5 Clinical Implications and Perspectives......Page 508
References......Page 509
15: The Pharmacology of Voltage-Gated Sodium Channels in Sensory Neurones......Page 518
1 Introduction......Page 519
1.1 VGSC Structure......Page 520
1.2 VGSC Function......Page 521
2 Classification, Distribution and Proposed Function of VGSC ?-Subunits in Peripheral Sensory Neurones......Page 522
2.5 NaV1.5......Page 523
2.8 NaV1.8 and NaV1.9......Page 524
3 Modulation of VGSCs in Sensory Neurones by Receptor Signalling Systems......Page 525
4.1 Local Anaesthetics......Page 528
4.2 Antiarrhythmic Drugs......Page 532
4.2.3 Class Ic......Page 533
4.2.5 Flecainide......Page 534
4.3 Anticonvulsants......Page 536
4.3.1 Anticonvulsants and Neuropathic Pain......Page 537
4.4 Toxins and Related Drugs......Page 538
4.4.1 ``Site 1´´ Toxins: TTX and Saxitoxin......Page 539
4.4.2 ``Site 1´´ Toxins: mu-Conotoxins......Page 541
4.4.3 ``Site 2´´ Toxins......Page 542
4.4.4 ``Sites 3-9´´ Toxins and Drugs......Page 544
4.5 Other Drugs......Page 546
5 Conclusion......Page 547
References......Page 548
16: Role of Calcium in Regulating Primary Sensory Neuronal Excitability......Page 561
1 Introduction......Page 562
3 Biophysical and Pharmacological Properties of Voltage-Gated Calcium Channels......Page 563
4 Calcium-Activated Currents......Page 566
4.2 IK Channel......Page 567
4.3 SK Channels......Page 568
4.4 Other Ca2+-Activated Potassium Currents......Page 570
5 Extracellular Calcium Sensor......Page 571
6 Calcium Regulation and Excitability......Page 572
6.1 Plasma Membrane Calcium ATPase......Page 573
6.3 Ryanodine Receptors......Page 575
6.5 Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase......Page 576
6.6 Mitochondria......Page 577
7.1 Chemotherapy-Induced Neuropathies......Page 578
8 Nerve Injury......Page 579
References......Page 580
17: Future Treatment Strategies for Neuropathic Pain......Page 586
1 Introduction......Page 587
2.1 Voltage-Gated Ion Channel Blockers......Page 588
2.2 Immune Cells and Their Released Factors in Neuropathic Pain......Page 591
2.2.1 Periphery......Page 592
2.2.2 Central......Page 593
2.2.3 Which Factors Released from Immune Cells Modulate Pain Processing?......Page 594
2.3 Protein Kinases......Page 595
2.4 Gene Therapy......Page 596
2.5.1 NGF as a Peripheral Pain Mediator......Page 598
2.5.2 BDNF as a Central Pain Mediator......Page 600
2.7 Cannabinoids......Page 602
2.8 Neurostimulation......Page 603
3 Conclusions......Page 604
References......Page 605
: Index......Page 613