Synaptic Plasticity in Pain (eBook)

About the Author:Dr. Marzia Malcangio holds a bachelors' degree in pharmaceutical chemistry and a PhD in Pharmacology from the University of Florence, Italy. She spent most of her active scientific life in London UK, establishing an internationally renowned laboratory devoted to the biology of spinal cord mechanisms underlying chronic pain. Her current work explores novel approaches for targeting neuropathic and arthritic pain unveiling, and the involvement of microglia and the mechanisms governing microglial-neuronal communication. Dr Malcangio lives in London with her husband and two sons.

Synaptic Plasticity in Pain 2
Contents 5
Contributors 8
Introduction 11
Part I Anatomical Plasticity of DorsalHorn Circuits 13
Changes in NK1 and Glutamate Receptors in Pain 14
1.1 Introduction 15
1.2 Anatomical Components of the Dorsal Horn 15
1.3 Substance P and the NK1r 16
1.3.1 Sources of Substance P in the Dorsal Horn 16
1.3.2 Anatomical Distribution of NK1r 16
1.3.3 Projection Neurons and the NK1r 17
1.3.4 Plasticity of NK1rs in the Dorsal Horn 18
1.4 Sources of Glutamatergic Input to the Dorsal Horn 20
1.5 Glutamate Receptors 20
1.5.1 Ionotropic Receptors at Glutamatergic Synapses 20
1.5.2 Metabotropic Glutamate Receptors 22
1.5.3 Plasticity Involving Glutamate Receptors 22
1.5.3.1 AMPA Receptors 22
1.5.3.2 NMDA Receptors 24
1.5.3.3 Metabotropic Glutamate Receptors 25
1.6 Concluding Remarks 25
References 26
Trophic Factors and Their Receptors in Pain Pathways 31
2.1 Introduction 32
2.2 Expression of Trophic Factors and Their Receptors by DRG Neurones 33
2.2.1 Subtypes of DRG Neurons 33
2.2.2 Peptidergic and Non-Peptidergic Nociceptors 34
2.2.3 Neurotrophins and Neurotrophin Receptors 37
2.2.4 GDNF Receptors 38
2.2.5 Neuropoietic Cytokines 40
2.3 Expression of Trophic Factors and Their Receptors by CNS Spinal Pain Pathways 42
2.4 GDNF in Inflammation and Nerve Injury 43
2.4.1 Inflammation 44
2.4.2 Nerve Injury 45
2.5 Concluding Remarks 46
References 46
Part IIFast Synaptic Transmission in the Dorsal Horn 56
Fast Inhibitory Transmission of Pain in the Spinal Cord 57
3.1 Introduction 58
3.2 Physiology of Inhibitory Neurotransmission in the Spinal Dorsal Horn 59
3.2.1 Distribution of GABAergic and Glycinergic Neurons in the Spinal Dorsal Horn 59
3.2.2 Integration of Inhibitory Dorsal Horn Neurons Dorsal Horn Circuits 60
3.2.3 Inhibitory Input to Dorsal Horn Neurons 62
3.2.4 Presynaptic Inhibition 63
3.3 Functional Consequences of Reduced Inhibitory Neurotransmission in the Spinal Dorsal Horn 63
3.3.1 Does a Loss of Synaptic Inhibition Occur Naturally In Vivo? 64
3.3.1.1 Inflammatory Pain 64
3.3.1.2 Neuropathic Pain 66
3.3.1.3 Activity-Dependent Sensitization 67
3.4 Restoring Synaptic Inhibition in Pathological Pain States 67
3.4.1 Subtype-Selective GABAA Receptor Ligands 67
3.4.2 Glycine Transporter Inhibitors 69
3.5 Concluding Remarks 69
References 70
Synaptic Transmission of Pain in the Developing Spinal Cord 75
4.1 Introduction - Development of Pain Transmission in Neonates 75
4.2 Excitatory Synaptic Transmission in the Developing Spinal Cord 77
4.2.1 AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) Receptors 77
4.2.2 KA (Kainate) Receptors 78
4.2.3 NMDA (N-methyl-D-aspartate) Receptors 78
4.3 Inhibitory Synaptic Transmission in the Developing Spinal Cord 79
4.3.1 Synthesis and Localisation of Inhibitory Neurotransmitters 80
4.3.2 Developmental Regulation of GABA AR and GlyR Stoichiometry 80
4.3.3 GABAA R and GlyR Synaptic Function in the Developing Dorsal Horn 81
4.3.4 Is GABA an Excitatory Neurotransmitter in the Immature Dorsal Horn? 83
4.3.5 Short Term Plasticity of GABAergic Transmission 85
4.4 Integration of Synaptic Inputs 86
4.5 Conclusion 87
References 88
Part III Slow Synaptic Transmission in the Dorsal Horn 94
BDNF and TrkB Mediated Mechanisms in the Spinal Cord 95
5.1 Introduction 96
5.2 Synthesis, Storage and Pattern of Expression of BDNF 97
5.3 Release of BDNF 97
5.4 Expression of BDNF Receptors (trkB) in Spinal Cord 98
5.5 Regulation of BDNF and Trk B Receptor Expression After Inflammation and Nerve Injury 102
5.6 Modulation of Synaptic Transmission by BDNF in Normal Animals and in Animal Models of Pain 103
5.6.1 Normal Animals 103
5.6.2 Inflammatory Pain 107
5.6.3 Neuropathic Pain 108
5.7 Concluding Remarks 110
References 110
Dorsal Horn Substance P and NK1 Receptors: Study of a Model System in Spinal Nociceptive Processing 115
6.1 Introduction 116
6.2 Substance P and Its Receptor in the Dorsal Horn 117
6.2.1 Substance P Synthesis 117
6.2.2 Origin of SP in Dorsal Horn 118
6.2.3 Tachykinin Receptors 119
6.3 Primary Afferent SP Release 120
6.4 Modulation of SP Release 121
6.4.1 Receptors Increasing SP Release 122
6.4.1.1 EP Receptors 122
6.4.1.2 P2X and P2Y 122
6.4.1.3 TRPV1/TRPA1 124
6.4.1.4 Bradykinin Receptors (B2) 125
6.4.1.5 NMDA 125
6.4.1.6 Voltage-Gated Calcium Channels 125
6.4.1.7 5-HT3 Receptor 126
6.4.1.8 TrkA 127
6.4.2 Receptors Reducing SP Release 127
6.4.2.1 mu/ Opiate Receptors 127
6.4.2.2 Adrenergic alpha2 Receptors 128
6.4.2.3 GABAA/B 128
6.4.2.4 Adenosine A1 129
6.4.2.5 CB1 129
6.4.2.6 NPY (Y1) 129
6.5 Role of SP/NK1 in Spinal Nociceptive Processing 129
6.5.1 Activation of Spinal NK1 Receptor 131
6.5.2 Inhibition of Spinal NK1 Receptor 131
6.5.3 Studies on Knockout Animals 131
6.5.4 Ablation of NK1 Bearing Cells 132
6.6 Concluding Remarks 133
References 133
Opioidergic Transmission in the Dorsal Horn 145
7.1 Introduction 146
7.2 ‘‘Classical’’ Opioid Receptors in the Dorsal Horn 147
7.2.1 Localization: Dorsal Horn Neurons and Primary Afferent Terminals 147
7.2.2 Opioid Receptor Signaling 149
7.2.3 Opioid Receptor Internalization, Trafficking and Synergism 150
7.2.4 Synergism Between MORs and DORs 151
7.2.5 Opioid Receptor Heterodimers 152
7.3 Atypical Opioid Receptors 152
7.3.1 Nociceptin Receptor 152
7.3.2 Opioid Growth Factor (OGF) Receptor 153
7.3.3 Toll-Like Receptors as Receptors for Opiate Drugs 153
7.4 Opioid Peptides in the Dorsal Horn 154
7.4.1 Endorphins 154
7.4.2 Enkephalins 155
7.4.3 Dynorphins 155
7.4.4 Endomorphins: Are They Really Endogenous? 156
7.4.5 Receptor Specificity: Is It Important? 157
7.5 Opioid Degradation by Peptidases 158
7.5.1 Peptidases that Degrade Opioids 158
7.5.2 Peptidase Inhibitors Used as Analgesics 159
7.5.3 The Opioid-Peptidase Paradox 160
7.5.4 Endogenous Peptidase Inhibitors 161
7.6 Neurotransmitter Receptors that Control Spinal Opioid Release 162
7.6.1 Adrenergic Receptors 162
7.6.2 Serotonin Receptors 162
7.6.3 NMDA Receptors 163
7.6.4 Receptors with No Effect or Unclear Effects on Opioid Release 163
7.7 Neural Pathways and Physiological Stimuli that Induce Spinal Opioid Release 163
7.7.1 Neural Pathways Involved in Spinal Opioid Release 163
7.7.2 Pain 164
7.7.3 Stress 165
7.7.4 Acupuncture 167
7.8 Conclusions 167
References 168
CGRP in Spinal Cord Pain Mechanisms 180
8.1 Introduction 181
8.2 CGRP and Its Receptors 181
8.3 Localization of CGRP and CGRP Receptors in the Spinal Cord 182
8.3.1 CGRP 182
8.3.2 CGRP Receptors 183
8.4 Pain-Related Changes in Spinal CGRP Neurochemistry 184
8.5 Electrophysiological Effects of Spinal CGRP 187
8.5.1 CGRP 187
8.5.2 CGRP Receptor Blockade 189
8.5.3 Supraspinal Consequences 192
8.6 Behavioral Effects of Spinal CGRP 193
8.6.1 CGRP 193
8.6.2 CGRP Receptor Blockade 195
8.6.3 Supraspinal Consequences 196
8.7 Concluding Remarks 196
References 197
Part IV Amplification of Pain-Related Information 203
Long-Term Potentiation in Superficial Spinal Dorsal Horn: A Pain Amplifier 204
9.1 Introduction 205
9.2 What is ‘‘LTP’’? 205
9.3 LTP and ‘‘Central Sensitisation’’ Are Not Equivalent 206
9.4 Methods to Assess LTP in Pain Pathways 207
9.5 LTP-Inducing Protocols 208
9.6 LTP at Synapses of Primary Afferent A-Fibres 212
9.7 Signalling Pathways of Spinal LTP 212
9.8 Prevention of LTP Induction 217
9.9 Long-Term Depression and Depotentiation 217
9.10 LTP in Pain Pathways Amplifies Pain Responses 217
9.11 Concluding Remarks 218
References 218
Modulation of Long-Term Potentiation of Excitatory Synaptic Transmission in the Spinal Cord Dorsal Horn 222
10.1 Introduction 223
10.2 NMDAR-Dependent LTP 224
10.3 Signal Transduction Mechanisms of LTP 227
10.3.1 Calcium/Calmodulin-Dependent Protein Kinase II Enhances AMPA/NMDA and Synaptic Responses of Rat DH Neurons 229
10.4 Central Sensitization 233
10.5 Role of PKC in LTP 234
10.6 The Role of PKA in LTP 235
10.7 LTP in the Spinal Dorsal Horn is Blocked by Tyrosine Kinase Inhibitor 238
10.8 Modulation of Primary Afferent Neurotransmission by Tachykinins Acting at Presynaptic and Postsynaptic Sites 240
10.8.1 Modulation of NMDA Responses in Acutely Isolated Rat Dorsal Horn Neurons by Tachykinins 243
10.8.2 Possible Cellular and Molecular Mechanisms of the SP Enhancement of NMDA Response 244
10.9 Enhanced LTP of Primary Afferent Neurotransmission in AMPA Receptor GluR2-Deficient Mice 246
10.10 Concluding Remarks 249
References 249
Windup in the Spinal Cord 258
11.1 Introduction 259
11.2 Windup and Central Sensitization 260
11.2.1 Pharmacology of Windup: Glutamate and Neuropeptides 261
11.2.2 Pharmacology of Windup: Neurotrophins 262
11.2.3 Pharmacology of Windup: Non-Synaptic Component 264
11.3 Concluding Remarks 265
References 266
Part V Mechanisms and Targets for Chronic Pain 271
Pain from the Arthritic Joint 272
12.1 Pain Sensations in the Joint 273
12.2 The Nociceptive Input from the Joint 273
12.2.1 Innervation of Joints 273
12.2.2 Response Properties of Joint Afferents and Peripheral Sensitization 274
12.2.3 Spinal Termination of Joint Afferents 274
12.3 Spinal Cord Neurons with Joint Input 275
12.3.1 Receptive Fields, Thresholds, Response Properties 275
12.3.2 Projections of Spinal Cord Neurons with Joint Input 277
12.3.3 Inhibition by Descending and Heterotopic Inhibitory Systems 277
12.3.4 Inflammation-Evoked Hyperexcitability of Spinal Cord Neurons with Joint Input 277
12.4 Molecular Mechanisms of Synaptic Excitation and Spinal Hyperexcitability 279
12.4.1 General Principles 279
12.4.2 Excitatory Amino Acids (Glutamate) 280
12.4.3 Neuropeptides 280
12.4.4 Spinal Prostaglandins 282
12.5 Conclusions 285
References 286
Spinal Mechanisms of Visceral Pain and Hyperalgesia 290
13.1 Introduction 291
13.2 An Animal Model to Address Visceral Pain and Hyperalgesia 293
13.3 Spinal Cord Mechanisms of Visceral Hypersensitivity 295
13.3.1 Chloride Co-Transporters and Visceral Hyperalgesic States 296
13.3.2 Visceral Hypersensitivity and AMPA Trafficking in the Spinal Cord 298
13.3.3 Role of Intracellular Signalling Kinases 301
13.4 Concluding Remarks 304
References 305
Descending Modulation of Pain 308
14.1 Introduction 309
14.2 Descending Modulatory Control and the Placebo Effect 311
14.3 Top-Down Modulation of Spinal Processing from the Brainstem 311
14.4 RVM Output Neurones 313
14.5 The RVM and Opioid Analgesia 315
14.6 RVM Neurones and Serotonin 315
14.7 Different 5HT Receptors Mediate the Differential Effects of Spinal Serotonin 317
14.8 The Spino-Bulbo-Spinal Loop 319
14.9 Anti-Depressants and Anti-Convulsants for the Treatment of Chronic Pain 319
14.10 Noradrenergic Inhibitory Pathways from the Brainstem 321
14.11 Descending Facilitations Influence Treatment Outcome and are Active in Different Models of Chronic Pain 322
14.12 Centrally Based Pains 327
14.13 Concluding Remarks 328
References 329
Cannabinoid Receptor Mediated Analgesia: Novel Targets for Chronic Pain States 337
15.1 Introduction 338
15.2 Multiple Sites of Action Mediate the Analgesic Effects of CB1 Agonists 338
15.3 Analgesic Potential for CB2 Receptor Agonists 339
15.4 Endocannabinoids 341
15.5 Endocannabinoids and Pain Processing 342
15.6 Facilitating Endocannabinoid-Mediated Analgesia 343
15.6.1 Targeting Fatty Acid Amide Hydrolase 344
15.6.2 Targeting Monoacylglycerol Lipase 344
15.7 Concluding Remarks 345
References 346
Spinal Dynorphin and Neuropathic Pain 352
16.1 Introduction 353
16.2 Structure-Activity Relationship of Dynorphin A 353
16.3 The Opioid and Non-Opioid Activities of Dynorphin A 354
16.4 Putative Non-Opioid Targets of Dynorphin A 355
16.5 The Pathophysiological Relevance of Agonist Actions of Dynorphin A at Bradykinin Receptors 356
16.6 Descending Pain Modulatory Pathway Is Essential for Spinal Dynorphin A Upregulation 358
16.7 Concluding Remarks 361
References 361
Microglia, Cytokines and Pain 366
17.1 Introduction 367
17.1.1 Physiological Pain Processing 367
17.1.2 Pathological Pain Processing: Neuropathic Pain 368
17.2 Glial Role in Neuropathic Pain 368
17.3 Cellular Signaling of TLR Activated Glia 369
17.4 Purinoreceptors: Glial Signals in Neuropathic Pain 371
17.5 A Unique Role for Innate Immune System Cells 372
17.6 Anti-Inflammatory Cytokines to Treat Neuropathic Pain 373
17.7 Interleukin-10 Trasngene Delivery to Control Pathological Pain 374
17.8 Innate Immune Cells in the Subarachnoid Matrix May Facilitate Transgene Delivery 376
17.9 A Copolymer of Lactic and Glycolic Acid, Poly(Lactic-co-Glycolic) (PLGA) for Targeted Spinal Cord Transgene IL-10 Delivery 377
17.10 Concluding Remarks 378
References 379
The Role of Astrocytes in the Modulation of Pain 386
18.1 Introduction 387
18.1.1 Astrocytes and Pain 387
18.2 Astrocytes and Synaptic Plasticity 389
18.3 Pain, Central Sensitization and the Role of Astrocyte Modulatory Strategies 392
18.4 Concluding Remarks 395
References 396
Spinal Cord Phospholipase A2 and Prostanoids in Pain Processing 402
19.1 Introduction 403
19.2 Spinal Actions of the PLA2/COX/Prostanoids Pathway in Hyperalgesia 404
19.3 Spinal Phospholipase A2 406
19.4 Calcium-Dependent Cytosolic PLA2 406
19.5 Expression of cPLA2 in the Spinal Cord 407
19.6 Is Inhibition of Spinal cPLA2 an Effective Target for Pain Relief? 408
19.7 Phosphorylation - An Additional Level of cPLA2 Activity Regulation 408
19.8 Calcium-Independent PLA2 409
19.9 Secretory PLA2 409
19.9.1 Secretory PLA2 in the Spinal Cord 410
19.9.2 Potential Non-Arachidonic Acid-Mediated Nociceptive Actions of sPLA2 410
19.10 Prostanoids and Prostanoid Receptors in Spinal Pain Signaling 411
19.10.1 Prostanoids in Cerebrospinal Fluid 411
19.10.2 Prostanoid Synthases 413
19.10.3 Prostanoid Receptors 413
19.11 Implications for Spinal PLA2 and Prostanoids as Drug Targets 414
19.12 Concluding Remarks 415
References 416
MAP Kinase and Cell Signaling in DRG Neurons and Spinal Microglia in Neuropathic Pain 423
20.1 Introduction 424
20.1.1 Peripheral and Central Sensitization After Nerve Injury 424
20.1.2 Neuronal-Glial Interaction and Central Sensitization 425
20.1.3 MAP Kinases and Peripheral and Central Sensitization 425
20.2 p38 MAP Kinase and Cell Signaling in DRG Neurons in Neuropathic Pain 426
20.2.1 p38 Activation in Intact DRG Neurons After Nerve Injury 427
20.2.2 p38 Activation in Injured DRG Neurons After Nerve Injury 428
20.3 p38 MAP Kinase and Cell Signaling in Spinal Microglia in Neuropathic Pain 429
20.3.1 p38 Activation in Spinal Cord Microglia and Neuropathic Pain 429
20.3.2 p38 and Spinal Cord Microglial Signaling After Nerve Injury 430
20.4 Concluding Remarks 432
References 432
Microglia and Trophic Factors in Neuropathic Pain States 437
21.1 Introduction 438
21.2 Microglial Activation Following Neuronal Injury 439
21.3 Role of ATP and P2X4 Receptor in Microglial Activation 441
21.4 BDNF as Signaling Molecule Between Microglia and Neurons 445
21.5 Concluding Remarks 448
References 448
The Cathepsin S/Fractalkine Pair: New Players in Spinal Cord Neuropathic Pain Mechanisms 452
22.1 Introduction 453
22.1.1 Biochemical Characteristics of Cathepsin S 453
22.2 Established Physiological Functions of Cathepsin S 454
22.2.1 Antigen Presentation 454
22.2.2 Tissue Remodelling and Extracellular Matrix Degradation 456
22.3 A New Role for Cathepsin S in Nociception 456
22.3.1 CatS is Expressed by Spinal Microglia 457
22.3.2 CatS Inhibition Attenuates Neuropathic Pain Behaviour 459
22.3.3 Exogenous CatS Induces Pain Behaviours 460
22.3.4 CatS Pro-Nociceptive Effects Are Mediated Via Fractalkine Cleavage 460
22.4 Concluding Remarks 463
References 464
Index 469