Malcangio Synaptic Plasticity in Pain

1. Auflage 2009
ISBN: 978-1-4419-0226-9
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 504 Seiten

Primary sensory neurons respond to peripheral stimulation and project to the spinal cord. Specifically, the population of neurons which respond to damaging stimuli terminate in the superficial layers of the dorsal horn. Therefore, the dorsal horns constitute the first relay site for nociceptive fibre terminals which make synaptic contacts with second order neurons. It has recently become clear that the strength of this first pain synapse is plastic and modifiable by several modulators, including neuronal and non-neuronal regulators, and studies on the fundamental processes regulating the plasticity of the first pain synapse have resulted in the identification of new targets for the treatment of chronic pain. This book will be of interest to a wide readership in the pain field.

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.

Autoren/Hrsg.

Malcangio, Marzia

Inhaltsverzeichnis

1;Synaptic Plasticity in Pain;2
1.1;Contents;5
1.2;Contributors;8
1.3;Introduction;11
1.4;Part I Anatomical Plasticity of DorsalHorn Circuits;13
1.4.1;Changes in NK1 and Glutamate Receptors in Pain;14
1.4.1.1;1.1 Introduction;15
1.4.1.2;1.2 Anatomical Components of the Dorsal Horn;15
1.4.1.3;1.3 Substance P and the NK1r;16
1.4.1.3.1;1.3.1 Sources of Substance P in the Dorsal Horn;16
1.4.1.3.2;1.3.2 Anatomical Distribution of NK1r;16
1.4.1.3.3;1.3.3 Projection Neurons and the NK1r;17
1.4.1.3.4;1.3.4 Plasticity of NK1rs in the Dorsal Horn;18
1.4.1.4;1.4 Sources of Glutamatergic Input to the Dorsal Horn;20
1.4.1.5;1.5 Glutamate Receptors;20
1.4.1.5.1;1.5.1 Ionotropic Receptors at Glutamatergic Synapses;20
1.4.1.5.2;1.5.2 Metabotropic Glutamate Receptors;22
1.4.1.5.3;1.5.3 Plasticity Involving Glutamate Receptors;22
1.4.1.5.3.1;1.5.3.1 AMPA Receptors;22
1.4.1.5.3.2;1.5.3.2 NMDA Receptors;24
1.4.1.5.3.3;1.5.3.3 Metabotropic Glutamate Receptors;25
1.4.1.6;1.6 Concluding Remarks;25
1.4.1.7;References;26
1.4.2;Trophic Factors and Their Receptors in Pain Pathways;31
1.4.2.1;2.1 Introduction;32
1.4.2.2;2.2 Expression of Trophic Factors and Their Receptors by DRG Neurones;33
1.4.2.2.1;2.2.1 Subtypes of DRG Neurons;33
1.4.2.2.2;2.2.2 Peptidergic and Non-Peptidergic Nociceptors;34
1.4.2.2.3;2.2.3 Neurotrophins and Neurotrophin Receptors;37
1.4.2.2.4;2.2.4 GDNF Receptors;38
1.4.2.2.5;2.2.5 Neuropoietic Cytokines;40
1.4.2.3;2.3 Expression of Trophic Factors and Their Receptors by CNS Spinal Pain Pathways;42
1.4.2.4;2.4 GDNF in Inflammation and Nerve Injury;43
1.4.2.4.1;2.4.1 Inflammation;44
1.4.2.4.2;2.4.2 Nerve Injury;45
1.4.2.5;2.5 Concluding Remarks;46
1.4.2.6;References;46
1.5;Part IIFast Synaptic Transmission in the Dorsal Horn;56
1.5.1;Fast Inhibitory Transmission of Pain in the Spinal Cord;57
1.5.1.1;3.1 Introduction;58
1.5.1.2;3.2 Physiology of Inhibitory Neurotransmission in the Spinal Dorsal Horn;59
1.5.1.2.1;3.2.1 Distribution of GABAergic and Glycinergic Neurons in the Spinal Dorsal Horn;59
1.5.1.2.2;3.2.2 Integration of Inhibitory Dorsal Horn Neurons Dorsal Horn Circuits;60
1.5.1.2.3;3.2.3 Inhibitory Input to Dorsal Horn Neurons;62
1.5.1.2.4;3.2.4 Presynaptic Inhibition;63
1.5.1.3;3.3 Functional Consequences of Reduced Inhibitory Neurotransmission in the Spinal Dorsal Horn;63
1.5.1.3.1;3.3.1 Does a Loss of Synaptic Inhibition Occur Naturally In Vivo?;64
1.5.1.3.1.1;3.3.1.1 Inflammatory Pain;64
1.5.1.3.1.2;3.3.1.2 Neuropathic Pain;66
1.5.1.3.1.3;3.3.1.3 Activity-Dependent Sensitization;67
1.5.1.4;3.4 Restoring Synaptic Inhibition in Pathological Pain States;67
1.5.1.4.1;3.4.1 Subtype-Selective GABAA Receptor Ligands;67
1.5.1.4.2;3.4.2 Glycine Transporter Inhibitors;69
1.5.1.5;3.5 Concluding Remarks;69
1.5.1.6;References;70
1.5.2;Synaptic Transmission of Pain in the Developing Spinal Cord;75
1.5.2.1;4.1 Introduction - Development of Pain Transmission in Neonates;75
1.5.2.2;4.2 Excitatory Synaptic Transmission in the Developing Spinal Cord;77
1.5.2.2.1;4.2.1 AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) Receptors;77
1.5.2.2.2;4.2.2 KA (Kainate) Receptors;78
1.5.2.2.3;4.2.3 NMDA (N-methyl-D-aspartate) Receptors;78
1.5.2.3;4.3 Inhibitory Synaptic Transmission in the Developing Spinal Cord;79
1.5.2.3.1;4.3.1 Synthesis and Localisation of Inhibitory Neurotransmitters;80
1.5.2.3.2;4.3.2 Developmental Regulation of GABA AR and GlyR Stoichiometry;80
1.5.2.3.3;4.3.3 GABAA R and GlyR Synaptic Function in the Developing Dorsal Horn;81
1.5.2.3.4;4.3.4 Is GABA an Excitatory Neurotransmitter in the Immature Dorsal Horn?;83
1.5.2.3.5;4.3.5 Short Term Plasticity of GABAergic Transmission;85
1.5.2.4;4.4 Integration of Synaptic Inputs;86
1.5.2.5;4.5 Conclusion;87
1.5.2.6;References;88
1.6;Part III Slow Synaptic Transmission in the Dorsal Horn;94
1.6.1;BDNF and TrkB Mediated Mechanisms in the Spinal Cord;95
1.6.1.1;5.1 Introduction;96
1.6.1.2;5.2 Synthesis, Storage and Pattern of Expression of BDNF;97
1.6.1.3;5.3 Release of BDNF;97
1.6.1.4;5.4 Expression of BDNF Receptors (trkB) in Spinal Cord;98
1.6.1.5;5.5 Regulation of BDNF and Trk B Receptor Expression After Inflammation and Nerve Injury;102
1.6.1.6;5.6 Modulation of Synaptic Transmission by BDNF in Normal Animals and in Animal Models of Pain;103
1.6.1.6.1;5.6.1 Normal Animals;103
1.6.1.6.2;5.6.2 Inflammatory Pain;107
1.6.1.6.3;5.6.3 Neuropathic Pain;108
1.6.1.7;5.7 Concluding Remarks;110
1.6.1.8;References;110
1.6.2;Dorsal Horn Substance P and NK1 Receptors: Study of a Model System in Spinal Nociceptive Processing;115
1.6.2.1;6.1 Introduction;116
1.6.2.2;6.2 Substance P and Its Receptor in the Dorsal Horn;117
1.6.2.2.1;6.2.1 Substance P Synthesis;117
1.6.2.2.2;6.2.2 Origin of SP in Dorsal Horn;118
1.6.2.2.3;6.2.3 Tachykinin Receptors;119
1.6.2.3;6.3 Primary Afferent SP Release;120
1.6.2.4;6.4 Modulation of SP Release;121
1.6.2.4.1;6.4.1 Receptors Increasing SP Release;122
1.6.2.4.1.1;6.4.1.1 EP Receptors;122
1.6.2.4.1.2;6.4.1.2 P2X and P2Y;122
1.6.2.4.1.3;6.4.1.3 TRPV1/TRPA1;124
1.6.2.4.1.4;6.4.1.4 Bradykinin Receptors (B2);125
1.6.2.4.1.5;6.4.1.5 NMDA;125
1.6.2.4.1.6;6.4.1.6 Voltage-Gated Calcium Channels;125
1.6.2.4.1.7;6.4.1.7 5-HT3 Receptor;126
1.6.2.4.1.8;6.4.1.8 TrkA;127
1.6.2.4.2;6.4.2 Receptors Reducing SP Release;127
1.6.2.4.2.1;6.4.2.1 mu/ Opiate Receptors;127
1.6.2.4.2.2;6.4.2.2 Adrenergic alpha2 Receptors;128
1.6.2.4.2.3;6.4.2.3 GABAA/B;128
1.6.2.4.2.4;6.4.2.4 Adenosine A1;129
1.6.2.4.2.5;6.4.2.5 CB1;129
1.6.2.4.2.6;6.4.2.6 NPY (Y1);129
1.6.2.5;6.5 Role of SP/NK1 in Spinal Nociceptive Processing;129
1.6.2.5.1;6.5.1 Activation of Spinal NK1 Receptor;131
1.6.2.5.2;6.5.2 Inhibition of Spinal NK1 Receptor;131
1.6.2.5.3;6.5.3 Studies on Knockout Animals;131
1.6.2.5.4;6.5.4 Ablation of NK1 Bearing Cells;132
1.6.2.6;6.6 Concluding Remarks;133
1.6.2.7;References;133
1.6.3;Opioidergic Transmission in the Dorsal Horn;145
1.6.3.1;7.1 Introduction;146
1.6.3.2;7.2 ‘‘Classical’’ Opioid Receptors in the Dorsal Horn;147
1.6.3.2.1;7.2.1 Localization: Dorsal Horn Neurons and Primary Afferent Terminals;147
1.6.3.2.2;7.2.2 Opioid Receptor Signaling;149
1.6.3.2.3;7.2.3 Opioid Receptor Internalization, Trafficking and Synergism;150
1.6.3.2.4;7.2.4 Synergism Between MORs and DORs;151
1.6.3.2.5;7.2.5 Opioid Receptor Heterodimers;152
1.6.3.3;7.3 Atypical Opioid Receptors;152
1.6.3.3.1;7.3.1 Nociceptin Receptor;152
1.6.3.3.2;7.3.2 Opioid Growth Factor (OGF) Receptor;153
1.6.3.3.3;7.3.3 Toll-Like Receptors as Receptors for Opiate Drugs;153
1.6.3.4;7.4 Opioid Peptides in the Dorsal Horn;154
1.6.3.4.1;7.4.1 Endorphins;154
1.6.3.4.2;7.4.2 Enkephalins;155
1.6.3.4.3;7.4.3 Dynorphins;155
1.6.3.4.4;7.4.4 Endomorphins: Are They Really Endogenous?;156
1.6.3.4.5;7.4.5 Receptor Specificity: Is It Important?;157
1.6.3.5;7.5 Opioid Degradation by Peptidases;158
1.6.3.5.1;7.5.1 Peptidases that Degrade Opioids;158
1.6.3.5.2;7.5.2 Peptidase Inhibitors Used as Analgesics;159
1.6.3.5.3;7.5.3 The Opioid-Peptidase Paradox;160
1.6.3.5.4;7.5.4 Endogenous Peptidase Inhibitors;161
1.6.3.6;7.6 Neurotransmitter Receptors that Control Spinal Opioid Release;162
1.6.3.6.1;7.6.1 Adrenergic Receptors;162
1.6.3.6.2;7.6.2 Serotonin Receptors;162
1.6.3.6.3;7.6.3 NMDA Receptors;163
1.6.3.6.4;7.6.4 Receptors with No Effect or Unclear Effects on Opioid Release;163
1.6.3.7;7.7 Neural Pathways and Physiological Stimuli that Induce Spinal Opioid Release;163
1.6.3.7.1;7.7.1 Neural Pathways Involved in Spinal Opioid Release;163
1.6.3.7.2;7.7.2 Pain;164
1.6.3.7.3;7.7.3 Stress;165
1.6.3.7.4;7.7.4 Acupuncture;167
1.6.3.8;7.8 Conclusions;167
1.6.3.9;References;168
1.6.4;CGRP in Spinal Cord Pain Mechanisms;180
1.6.4.1;8.1 Introduction;181
1.6.4.2;8.2 CGRP and Its Receptors;181
1.6.4.3;8.3 Localization of CGRP and CGRP Receptors in the Spinal Cord;182
1.6.4.3.1;8.3.1 CGRP;182
1.6.4.3.2;8.3.2 CGRP Receptors;183
1.6.4.4;8.4 Pain-Related Changes in Spinal CGRP Neurochemistry;184
1.6.4.5;8.5 Electrophysiological Effects of Spinal CGRP;187
1.6.4.5.1;8.5.1 CGRP;187
1.6.4.5.2;8.5.2 CGRP Receptor Blockade;189
1.6.4.5.3;8.5.3 Supraspinal Consequences;192
1.6.4.6;8.6 Behavioral Effects of Spinal CGRP;193
1.6.4.6.1;8.6.1 CGRP;193
1.6.4.6.2;8.6.2 CGRP Receptor Blockade;195
1.6.4.6.3;8.6.3 Supraspinal Consequences;196
1.6.4.7;8.7 Concluding Remarks;196
1.6.4.8;References;197
1.7;Part IV Amplification of Pain-Related Information;203
1.7.1;Long-Term Potentiation in Superficial Spinal Dorsal Horn: A Pain Amplifier;204
1.7.1.1;9.1 Introduction;205
1.7.1.2;9.2 What is ‘‘LTP’’?;205
1.7.1.3;9.3 LTP and ‘‘Central Sensitisation’’ Are Not Equivalent;206
1.7.1.4;9.4 Methods to Assess LTP in Pain Pathways;207
1.7.1.5;9.5 LTP-Inducing Protocols;208
1.7.1.6;9.6 LTP at Synapses of Primary Afferent A-Fibres;212
1.7.1.7;9.7 Signalling Pathways of Spinal LTP;212
1.7.1.8;9.8 Prevention of LTP Induction;217
1.7.1.9;9.9 Long-Term Depression and Depotentiation;217
1.7.1.10;9.10 LTP in Pain Pathways Amplifies Pain Responses;217
1.7.1.11;9.11 Concluding Remarks;218
1.7.1.12;References;218
1.7.2;Modulation of Long-Term Potentiation of Excitatory Synaptic Transmission in the Spinal Cord Dorsal Horn;222
1.7.2.1;10.1 Introduction;223
1.7.2.2;10.2 NMDAR-Dependent LTP;224
1.7.2.3;10.3 Signal Transduction Mechanisms of LTP;227
1.7.2.3.1;10.3.1 Calcium/Calmodulin-Dependent Protein Kinase II Enhances AMPA/NMDA and Synaptic Responses of Rat DH Neurons;229
1.7.2.4;10.4 Central Sensitization;233
1.7.2.5;10.5 Role of PKC in LTP;234
1.7.2.6;10.6 The Role of PKA in LTP;235
1.7.2.7;10.7 LTP in the Spinal Dorsal Horn is Blocked by Tyrosine Kinase Inhibitor;238
1.7.2.8;10.8 Modulation of Primary Afferent Neurotransmission by Tachykinins Acting at Presynaptic and Postsynaptic Sites;240
1.7.2.8.1;10.8.1 Modulation of NMDA Responses in Acutely Isolated Rat Dorsal Horn Neurons by Tachykinins;243
1.7.2.8.2;10.8.2 Possible Cellular and Molecular Mechanisms of the SP Enhancement of NMDA Response;244
1.7.2.9;10.9 Enhanced LTP of Primary Afferent Neurotransmission in AMPA Receptor GluR2-Deficient Mice;246
1.7.2.10;10.10 Concluding Remarks;249
1.7.2.11;References;249
1.7.3;Windup in the Spinal Cord;258
1.7.3.1;11.1 Introduction;259
1.7.3.2;11.2 Windup and Central Sensitization;260
1.7.3.2.1;11.2.1 Pharmacology of Windup: Glutamate and Neuropeptides;261
1.7.3.2.2;11.2.2 Pharmacology of Windup: Neurotrophins;262
1.7.3.2.3;11.2.3 Pharmacology of Windup: Non-Synaptic Component;264
1.7.3.3;11.3 Concluding Remarks;265
1.7.3.4;References;266
1.8;Part V Mechanisms and Targets for Chronic Pain;271
1.8.1;Pain from the Arthritic Joint;272
1.8.1.1;12.1 Pain Sensations in the Joint;273
1.8.1.2;12.2 The Nociceptive Input from the Joint;273
1.8.1.2.1;12.2.1 Innervation of Joints;273
1.8.1.2.2;12.2.2 Response Properties of Joint Afferents and Peripheral Sensitization;274
1.8.1.2.3;12.2.3 Spinal Termination of Joint Afferents;274
1.8.1.3;12.3 Spinal Cord Neurons with Joint Input;275
1.8.1.3.1;12.3.1 Receptive Fields, Thresholds, Response Properties;275
1.8.1.3.2;12.3.2 Projections of Spinal Cord Neurons with Joint Input;277
1.8.1.3.3;12.3.3 Inhibition by Descending and Heterotopic Inhibitory Systems;277
1.8.1.3.4;12.3.4 Inflammation-Evoked Hyperexcitability of Spinal Cord Neurons with Joint Input;277
1.8.1.4;12.4 Molecular Mechanisms of Synaptic Excitation and Spinal Hyperexcitability;279
1.8.1.4.1;12.4.1 General Principles;279
1.8.1.4.2;12.4.2 Excitatory Amino Acids (Glutamate);280
1.8.1.4.3;12.4.3 Neuropeptides;280
1.8.1.4.4;12.4.4 Spinal Prostaglandins;282
1.8.1.5;12.5 Conclusions;285
1.8.1.6;References;286
1.8.2;Spinal Mechanisms of Visceral Pain and Hyperalgesia;290
1.8.2.1;13.1 Introduction;291
1.8.2.2;13.2 An Animal Model to Address Visceral Pain and Hyperalgesia;293
1.8.2.3;13.3 Spinal Cord Mechanisms of Visceral Hypersensitivity;295
1.8.2.3.1;13.3.1 Chloride Co-Transporters and Visceral Hyperalgesic States;296
1.8.2.3.2;13.3.2 Visceral Hypersensitivity and AMPA Trafficking in the Spinal Cord;298
1.8.2.3.3;13.3.3 Role of Intracellular Signalling Kinases;301
1.8.2.4;13.4 Concluding Remarks;304
1.8.2.5;References;305
1.8.3;Descending Modulation of Pain;308
1.8.3.1;14.1 Introduction;309
1.8.3.2;14.2 Descending Modulatory Control and the Placebo Effect;311
1.8.3.3;14.3 Top-Down Modulation of Spinal Processing from the Brainstem;311
1.8.3.4;14.4 RVM Output Neurones;313
1.8.3.5;14.5 The RVM and Opioid Analgesia;315
1.8.3.6;14.6 RVM Neurones and Serotonin;315
1.8.3.7;14.7 Different 5HT Receptors Mediate the Differential Effects of Spinal Serotonin;317
1.8.3.8;14.8 The Spino-Bulbo-Spinal Loop;319
1.8.3.9;14.9 Anti-Depressants and Anti-Convulsants for the Treatment of Chronic Pain;319
1.8.3.10;14.10 Noradrenergic Inhibitory Pathways from the Brainstem;321
1.8.3.11;14.11 Descending Facilitations Influence Treatment Outcome and are Active in Different Models of Chronic Pain;322
1.8.3.12;14.12 Centrally Based Pains;327
1.8.3.13;14.13 Concluding Remarks;328
1.8.3.14;References;329
1.8.4;Cannabinoid Receptor Mediated Analgesia: Novel Targets for Chronic Pain States;337
1.8.4.1;15.1 Introduction;338
1.8.4.2;15.2 Multiple Sites of Action Mediate the Analgesic Effects of CB1 Agonists;338
1.8.4.3;15.3 Analgesic Potential for CB2 Receptor Agonists;339
1.8.4.4;15.4 Endocannabinoids;341
1.8.4.5;15.5 Endocannabinoids and Pain Processing;342
1.8.4.6;15.6 Facilitating Endocannabinoid-Mediated Analgesia;343
1.8.4.6.1;15.6.1 Targeting Fatty Acid Amide Hydrolase;344
1.8.4.6.2;15.6.2 Targeting Monoacylglycerol Lipase;344
1.8.4.7;15.7 Concluding Remarks;345
1.8.4.8;References;346
1.8.5;Spinal Dynorphin and Neuropathic Pain;352
1.8.5.1;16.1 Introduction;353
1.8.5.2;16.2 Structure-Activity Relationship of Dynorphin A;353
1.8.5.3;16.3 The Opioid and Non-Opioid Activities of Dynorphin A;354
1.8.5.4;16.4 Putative Non-Opioid Targets of Dynorphin A;355
1.8.5.5;16.5 The Pathophysiological Relevance of Agonist Actions of Dynorphin A at Bradykinin Receptors;356
1.8.5.6;16.6 Descending Pain Modulatory Pathway Is Essential for Spinal Dynorphin A Upregulation;358
1.8.5.7;16.7 Concluding Remarks;361
1.8.5.8;References;361
1.8.6;Microglia, Cytokines and Pain;366
1.8.6.1;17.1 Introduction;367
1.8.6.1.1;17.1.1 Physiological Pain Processing;367
1.8.6.1.2;17.1.2 Pathological Pain Processing: Neuropathic Pain;368
1.8.6.2;17.2 Glial Role in Neuropathic Pain;368
1.8.6.3;17.3 Cellular Signaling of TLR Activated Glia;369
1.8.6.4;17.4 Purinoreceptors: Glial Signals in Neuropathic Pain;371
1.8.6.5;17.5 A Unique Role for Innate Immune System Cells;372
1.8.6.6;17.6 Anti-Inflammatory Cytokines to Treat Neuropathic Pain;373
1.8.6.7;17.7 Interleukin-10 Trasngene Delivery to Control Pathological Pain;374
1.8.6.8;17.8 Innate Immune Cells in the Subarachnoid Matrix May Facilitate Transgene Delivery;376
1.8.6.9;17.9 A Copolymer of Lactic and Glycolic Acid, Poly(Lactic-co-Glycolic) (PLGA) for Targeted Spinal Cord Transgene IL-10 Delivery;377
1.8.6.10;17.10 Concluding Remarks;378
1.8.6.11;References;379
1.8.7;The Role of Astrocytes in the Modulation of Pain;386
1.8.7.1;18.1 Introduction;387
1.8.7.1.1;18.1.1 Astrocytes and Pain;387
1.8.7.2;18.2 Astrocytes and Synaptic Plasticity;389
1.8.7.3;18.3 Pain, Central Sensitization and the Role of Astrocyte Modulatory Strategies;392
1.8.7.4;18.4 Concluding Remarks;395
1.8.7.5;References;396
1.8.8;Spinal Cord Phospholipase A2 and Prostanoids in Pain Processing;402
1.8.8.1;19.1 Introduction;403
1.8.8.2;19.2 Spinal Actions of the PLA2/COX/Prostanoids Pathway in Hyperalgesia;404
1.8.8.3;19.3 Spinal Phospholipase A2;406
1.8.8.4;19.4 Calcium-Dependent Cytosolic PLA2;406
1.8.8.5;19.5 Expression of cPLA2 in the Spinal Cord;407
1.8.8.6;19.6 Is Inhibition of Spinal cPLA2 an Effective Target for Pain Relief?;408
1.8.8.7;19.7 Phosphorylation - An Additional Level of cPLA2 Activity Regulation;408
1.8.8.8;19.8 Calcium-Independent PLA2;409
1.8.8.9;19.9 Secretory PLA2;409
1.8.8.9.1;19.9.1 Secretory PLA2 in the Spinal Cord;410
1.8.8.9.2;19.9.2 Potential Non-Arachidonic Acid-Mediated Nociceptive Actions of sPLA2;410
1.8.8.10;19.10 Prostanoids and Prostanoid Receptors in Spinal Pain Signaling;411
1.8.8.10.1;19.10.1 Prostanoids in Cerebrospinal Fluid;411
1.8.8.10.2;19.10.2 Prostanoid Synthases;413
1.8.8.10.3;19.10.3 Prostanoid Receptors;413
1.8.8.11;19.11 Implications for Spinal PLA2 and Prostanoids as Drug Targets;414
1.8.8.12;19.12 Concluding Remarks;415
1.8.8.13;References;416
1.8.9;MAP Kinase and Cell Signaling in DRG Neurons and Spinal Microglia in Neuropathic Pain;423
1.8.9.1;20.1 Introduction;424
1.8.9.1.1;20.1.1 Peripheral and Central Sensitization After Nerve Injury;424
1.8.9.1.2;20.1.2 Neuronal-Glial Interaction and Central Sensitization;425
1.8.9.1.3;20.1.3 MAP Kinases and Peripheral and Central Sensitization;425
1.8.9.2;20.2 p38 MAP Kinase and Cell Signaling in DRG Neurons in Neuropathic Pain;426
1.8.9.2.1;20.2.1 p38 Activation in Intact DRG Neurons After Nerve Injury;427
1.8.9.2.2;20.2.2 p38 Activation in Injured DRG Neurons After Nerve Injury;428
1.8.9.3;20.3 p38 MAP Kinase and Cell Signaling in Spinal Microglia in Neuropathic Pain;429
1.8.9.3.1;20.3.1 p38 Activation in Spinal Cord Microglia and Neuropathic Pain;429
1.8.9.3.2;20.3.2 p38 and Spinal Cord Microglial Signaling After Nerve Injury;430
1.8.9.4;20.4 Concluding Remarks;432
1.8.9.5;References;432
1.8.10;Microglia and Trophic Factors in Neuropathic Pain States;437
1.8.10.1;21.1 Introduction;438
1.8.10.2;21.2 Microglial Activation Following Neuronal Injury;439
1.8.10.3;21.3 Role of ATP and P2X4 Receptor in Microglial Activation;441
1.8.10.4;21.4 BDNF as Signaling Molecule Between Microglia and Neurons;445
1.8.10.5;21.5 Concluding Remarks;448
1.8.10.6;References;448
1.8.11;The Cathepsin S/Fractalkine Pair: New Players in Spinal Cord Neuropathic Pain Mechanisms;452
1.8.11.1;22.1 Introduction;453
1.8.11.1.1;22.1.1 Biochemical Characteristics of Cathepsin S;453
1.8.11.2;22.2 Established Physiological Functions of Cathepsin S;454
1.8.11.2.1;22.2.1 Antigen Presentation;454
1.8.11.2.2;22.2.2 Tissue Remodelling and Extracellular Matrix Degradation;456
1.8.11.3;22.3 A New Role for Cathepsin S in Nociception;456
1.8.11.3.1;22.3.1 CatS is Expressed by Spinal Microglia;457
1.8.11.3.2;22.3.2 CatS Inhibition Attenuates Neuropathic Pain Behaviour;459
1.8.11.3.3;22.3.3 Exogenous CatS Induces Pain Behaviours;460
1.8.11.3.4;22.3.4 CatS Pro-Nociceptive Effects Are Mediated Via Fractalkine Cleavage;460
1.8.11.4;22.4 Concluding Remarks;463
1.8.11.5;References;464
1.9;Index;469