1 Animal Models of Analgesia.- A. Introduction.- B. Animal Models and Ethics.- C. Factors Affecting Measurements of Nociception.- D. Tests of Nociception and Analgesia.- I. Direct Measurements of Pain, Behavioural Responses.- 1. Acute Stimulation of Nociceptors.- 2. Intrathecal Injection of Nociceptive Neurotransmitters.- 3. Long-Term Peripheral Stimulation.- 4. Models of Neuropathic Pain.- 5. Models of Central Pain.- II. Physiological Correlates of Pain or Nociception.- 1. Electrophysiological Methods.- 2. Biochemical and Histochemical Methods.- E. Comparative Aspects.- F. Conclusion.- References.- 2 Peripheral Mediators of Pain.- A. Introduction.- B. Chemical Signalling in Fine Afferent Neurones.- C. Mediators Generated by Tissue Damage and Inflammation.- D. Mediators Released from Neurones.- E. Inflammatory Mediators from Immune Cells.- F. Exogenous Modulators of Sensory Fibre Activity: Vanilloids (Capsaicin Analogues).- G. Ion Channels Activity and Chronic Pain.- H. Summary.- References.- 3 Non-steroidal Anti-inflammatory Drugs and Pain.- A. Inflammatory Pain and NSAIDs.- B. Cyclo-oxygenase.- I. Isoforms of Cyclo-oxygenase.- 1. Cyclo-oxygenase 1.- 2. Cyclo-oxygenase 2.- II. Cyclo-oxygenase Isoforms and Inflammation.- 1. Selective Inhibitors of Cyclo-oxygenase Isoforms and Inflammation.- III. Side Effects of NSAID Therapy.- C. Prostaglandins and Inflammatory Pain.- I. Non-steroidal Anti-inflammatory Drugs and Inflammatory Pain.- 1. Selective Inhibition of COX-2 and Inflammatory Pain.- II. Prostaglandins and Central Nociceptive Processing.- 1. COX-2 in the Central Nervous System.- III. Analgesic and Anti-inflammatory Effects of NSAIDs Separate from Inhibition of Peripheral PG Formation.- 1. NSAIDs and Substance P.- 2. NSAIDs and Immediate-Early Genes.- 3. NSAIDs and Apoptosis.- D. Nitric Oxide and Nociception.- I. Analgesic Properties of NO.- II. Hyperalgesic Properties of NO.- 1. Nitric Oxide in Thermal and Mechanical Hyperalgesia.- III. Effect of NSAIDs on NOS.- IV. Interaction of PGs and NO.- V. Interactions Between NOS and HO.- E. Conclusion.- References.- 4 The Sympathetic Nervous System and Pain.- A. Introduction.- B. The Emergence of the Concept of an Interaction Between the Sympathetic and the Somatosensory System.- I. The Key Clinical Findings in Patients with SMP.- C. Sympathetic Activation Has a Negligible Effect on Normal Sensory Processing.- D. Several Interactions Between the Sympathetic and the Nociceptive Systems Develop After Nerve Injury.- I. Animal Models of Neuropathic and Sympathetically Maintained Pain.- II. Sprouts of Axotomised Afferents Projecting into a Neuroma.- III. Primary Afferents Projecting into a Partially Damaged Nerve.- IV. Interactions Between Sympathetic Fibres and Primary Afferent Neurones in the Dorsal Root Ganglion.- V. Are Changes in the Sympathetic Nervous System Necessary To Permit the Interaction with Primary Afferent Fibres?.- E. Can the Sympathetic Nervous System Modulate Pain and Hyperalgesia Under Inflammatory Conditions?.- I. The Contribution of Sympathetic Fibres to Inflammation.- II. The Contribution of Sympathetic Fibres to Nociceptive Behaviour.- References.- 5 Excitability Blockers: Anticonvulsants and Low Concentration Local Anesthetics in the Treatment of Chronic Pain.- A. Introduction.- B. Anticonvulsants in the Treatment of Neuropathic Pain.- I. Trigeminal Neuralgia (Tic Doloreux).- II. Other Painful Conditions Responding to Anticonvulsants.- III. Clinical Use of Anticonvulsants.- 1. Carbamazepine.- 2. Phenytoin.- 3. Clonazepam.- 4. Valproic Acid.- 5. Gabapentin.- 6. Lamotrigine.- C. Systemically Administered Local Anesthetics in the Treatment of Neuropathic Pain.- I. Conditions Responding to Systemic Local Anesthetics.- II. Which Local Anesthetic To Choose?.- 1. Intravenous Lidocaine.- 2. Oral Local Anesthetic Antiarrhythmics.- III. Topical Local Anesthetics for Chronic Pain.- D. Mechanisms of Action: Anticonvulsants and Local Anesthetics Suppress Abnormal Primary Afferent Firing.- I. Evidence that Abnormal Afferent Firing Contributes to Neuropathic Pain, and that Membrane-Stabilizing Drugs Suppress This Activity.- 1. Sources of Ectopic Firing.- 2. Ectopic Firing and Pain.- II. Clinical Evidence that Abnormal Afferent Firing Contributes to Neuropathic Pain.- III. Mechanisms by Which Membrane-Stabilizing Drugs Suppress Ectopic Neural Activity.- 1. Na+ Channels.- 2. Basis for Selectivity.- 3. Does Analgesia Result from Suppression of PNS or CNS Activity or Both?.- 4. Strategies for Reducing Dose-Limiting Side Effects of Systemic Membrane-Stabilizing Drugs.- E. Summary.- References.- 6 Tachykinins: Central and Peripheral Effects.- A. Introduction.- B. Substance P and NK-1 Receptors.- I. Association with Sensory Systems.- II. Pathophysiology.- III. Substance P and NK-1 Receptors in Man.- C. NK-1 Receptor Antagonists.- D. Therapeutic Potential of Drugs Acting at NK-1 Receptors.- I. Acute and Chronic Pain.- 1. Extravasation/Inflammation Models.- 2. Electrophysiological Models.- 3. Behavioural Models.- 4. Visceral Pain.- II. Migraine.- III. Emesis.- E. Summary.- References.- 7 Growth Factors and Pain.- A. Introduction.- B. NGF and Its Receptors.- C. NGF as A Mediator of Persistent Pain.- I. NGF Maintains Nociceptor Sensitivity In Vivo.- II. Expression of NGF in Inflammatory States.- III. Expression of NGF Receptors on Nociceptors.- IV. Hyperalgesic Effects of Exogenous NGF.- V. Sensitisation of Nociceptors by Exogenous NGF.- VI. Anti-hyperalgesic Effects of NGF Antagonism.- D. Mechanisms of NGF-Induced Hyperalgesia.- I. Peripheral Sensitisation.- II. Central Sensitisation.- E. Growth Factors and Neuropathic Pain.- I. NGF Interacts with Adult Sensory and Sympathetic Neurones.- II. Altered Availability of NGF in Neuropathy.- III. Death of Injured Sensory Neurones.- IV. Altered Gene Expression in Damaged Sensory Neurones.- V. Axon Calibre/Conduction Velocity Changes with Damage.- VI. Changes in the Sympathetic Nervous System After Nerve Injury.- VII. Dorsal Horn Changes After Nerve Injury.- VIII. Other Growth Factors and Neuropathic Pain.- F. Conclusions.- References.- 8 Mechanisms of Central Hypersensitivity: Excitatory Amino Acid Mechanisms and Their Control.- A. Central Hypersensitivity.- I. Wind-Up and Central Hypersensitivity.- B. Substrates for Central Hypersensitivity.- I. Peptides.- II. Excitatory Amino Acids.- 1. Excitatory Amino Acid Receptors.- C. Mechanisms of Central Hypersensitivity.- I. Wind-Up.- II. Evidence for a Role of the AMPA Receptor.- III. Evidence for a Role of the Metabotropic Receptor.- IV. Evidence for a Role of the NMDA Receptor.- D. NMDA Antagonists and Spinal Hypersensitivity in Persistent Pain States.- I. Gene Induction.- II. Inflammatory Hyperalgesia and NMDA Receptors.- III. Neuropathic Pain States and NMDA Receptors.- E. Controlling NMDA Receptor Activation.- I. Clinical Use of NMDA Antagonists.- II. Peripheral Block of Afferent Activity.- III. NMDA Receptor Antagonists in Combination with Opioids.- F. Indirect Influences on NMDA Receptor Activation.- I. Nitric Oxide as a Target.- II. Increasing Inhibitory Controls.- III. Adenosine as a Target.- IV. GABA as a Target.- G. Conclusions.- References.- 9 Novel Modulators in Nociception.- A. Introduction.- B. Nitric Oxide.- I. Nitric Oxide Synthase.- II. Distribution of NOS in Pathways Related to Nociception.- 1. Dorsal Root Ganglia.- 2. Spinal Cord.- 3. Plasticity of NOS Activity in Nociceptive Pathways After Injury.- III. Evidence for the Involvement of NO in Nociception.- 1. Periphery.- 2. Spinal Cord.- 3. Supraspinal Sites.- IV. NO and Chronic Pain.- V. NO and Opioid Analgesia.- VI. Therapeutic Potentials of NOS Inhibitors.- C. Cholecystokinin.- I. Distribution of CCK in Nociceptive Pathways.- 1. Dorsal Root Ganglia.- 2. Spinal Cord.- 3. Supraspinal Sites.- II. CCK Receptors.- 1. Classification of CCK Receptor Subtypes.- 2. CCK Receptors in the Spinal Cord.- 3. CCK Receptor Antagonists.- III. Plasticity of Spinal CCK Systems After Injury.- IV. CCK in Nociception.- 1. CCK and Opioid-Mediated Analgesia.- 2. CCK and Opioid Tolerance.- 3. CCK and Opioid Sensitivity.- 4. Other Effects of CCK Related to Nociception.- V. Therapeutic Potentials for CCK Receptor Related Compounds.- D. Galanin.- I. Distribution of Galanin and Galanin Receptors in Sensory Neurons and Spinal Cord: Response to Injury.- 1. Dorsal Root Ganglia.- 2. Spinal Cord.- II. Involvement of Galanin in Nociception Under Normal Conditions.- 1. Behavioral Studies.- 2. Electrophysiological Studies.- 3. Pharmacology and Mechanisms of the Spinal Effects of Galanin.- III. Involvement of Galanin in Nociception After Peripheral Nerve Injury.- References.- 10 Pharmacological Studies of Nociceptive Systems Using the C-Fos Immunohistochemical Technique: An Indicator of Noxiously Activated Spinal Neurones.- A. Introduction.- B. Spinal Expression of c-Fos: Physiological Aspects.- I. Acute Noxious Stimulation.- II. Persistent Chronic Nociception.- III. c-Fos: The Unknown Factors.- IV. c-Fos: Experimental and Technical Considerations.- C. Pharmacological Aspects.- I. Opioids.- II. Spinal Transmitter Interactions.- 1. Morphine and Cholecytokinin.- 2. Co-administration of a Full Inhibitor of Enkephalin Catabolizing Enzymes and a CCKB Receptor Antagonist.- 3. Co-administration of an ?2-Adrenoceptor Agonist and Morphine.- 4. Co-administration of Morphine and an NMDA Receptor Antagonist.- III. Manipulation of Spinal Excitatory Transmitter Systems.- 1. The Contribution of NMDA Receptor Mediated Events to Spinal c-Fos Expression.- 2. The Contribution of Substance P to Spinal c-Fos Expression.- 3. Do Interactions Between NMDA Receptor and Substance P Receptor Mediated Events Influence Spinal c-Fos Expression?.- 4. The Nitric Oxide System.- IV. Nonsteroidal Anti-inflammatory Drugs and Paracetamol.- D. Conclusion.- References.- 11 Molecular Aspect of Opioid Receptors.- A. Introduction.- B. cDNA Cloning of Opioid Receptors.- I. The (?-Opioid Receptor: First Receptor Cloned by Expression Cloning.- II. The ?- and ?-Opioid Receptors: Cloning by Homology with the ? -Opioid Receptor.- III. Pharmacological Properties of the Cloned DOR, MOR and KOR Receptors.- IV. Signalling Properties of the Cloned DOR, MOR and KOR Receptors.- C. cDNA Cloning of an Opioid-like Orphan Receptor.- D. Structural Features of the Opioid Receptor Family.- I. Homology Pattern.- II. Ligand Binding and Transduction.- III. Posttranslational Modification Signals.- IV. Conservation Across Species.- E. Opioid Receptor Genes.- I. Chromosomal Assignment.- II. Genomic Organization.- III. Initiation of Transcription.- IV. Genomic Cloning and Perpectives.- F. Conclusion: Reconciling Pharmacology and Gene Cloning?.- References.- 12 Opioid Pharmacology of Acute and Chronic Pain.- A. Introduction.- B. Pharmacological Characterization.- I. Opioids and CCK in Nociception.- II. Modulation of Opioid Activity by ? Agonists.- C. Physiological Roles.- I. Opioids, CCK, and Inflammation.- II. Opioids and Inhibitory Tone.- 1. Role of Endogenous Opioids in Modulation of Tonic Nociceptive Input.- 2. Involvement of Immediate-Early Onset Genes in Opioid Modulation of Tonic Nociception.- D. Pathological Roles: Opioids and Neuropathic Pain.- I. Clinical Significance of Neuropathic Pain States.- II. Proposed Mechanisms of Neuropathic Pain.- III. Opioids in Neuropathic Pain.- 1. Development of Tolerance.- 2. Location of Opioid Receptors.- 3. Change in Relevant Receptors/Afferent Fibers.- 4. Loss of Spinal/Supraspinal Morphine Synergy.- 5. Afferent Drive.- 6. Upregulation of Endogenous Antiopioid Substances.- IV. Pathological Role of Dynorphin.- 1. Allodynic Effects of Exogenous Administration of a Single Intrathecal Injection of Dynorphin or Its des-Tyr Fragments: Blockade by MK-801 and Not Naloxone.- 2. Antisera to (Intrathecal) Dynorphin Restores the Antiallodynic and Enhances the Antinociceptive Efficacy of Intrathecal Morphine.- E. Conclusions.- References.- 13 Opioid Problems, and Morphine Metabolism and Excretion.- A. Clinical Aspects.- I. Effectiveness.- 1. Neuropathic Pain.- II. Red Herrings.- 1. Tolerance.- 2. Addiction.- B. Morphine and Metabolites.- I. What Are They?.- 1. Chemistry.- 2. Analysis.- II. How Are They Made? Enzymology.- 1. Liver.- 2. Kidney.- 3. Central Nervous System.- III. Where Are They Found?.- 1. Urine Studies.- 2. Plasma.- 3. Central Nervous System.- IV. What Do They Do? Pharmacology.- 1. Morphine-3-Glucuronide.- 2. Morphine-6-Glucuronide.- 3. Morphine and Metabolites: Plasma and CSF Ratios.- 4. Clinical Effects.- V. Pathophysiology.- 1. Liver Disease.- 2. Kidney Disease.- 3. Drug Interactions.- C. Conclusions.- References.- 14 Inhibitory Neurotransmitters and Nociception: Role of GABA and Glycine.- A. Introduction.- B. GABA.- I. Molecular Biology, Pharmacology, and Distribution.- 1. Molecular Biology.- 2. Pharmacology.- 3. Distribution in the Central Nervous System.- II. Role of GABA in Nociceptive Processing at the Level of the Spinal Cord.- 1. Studies of Acute Nociception.- 2. Studies of Persistent or Neuropathic Pain.- III. GABAergic Modulation of Supraspinal Nuclei.- 1. GABAA Receptors.- 2. GABAB Receptors.- 3. Role of GABA in the Antinociceptive Effects of Morphine.- C. Glycine.- I. Molecular Biology and Pharmacology.- II. Role of Glycine in Nociceptive Processing at the Level of the Spinal Cord.- III. Role of Glycine at Supraspinal Nuclei.- D. Summary.- References.- 15 The Role of Descending Noradrenergic and Serotoninergic Pathways in the Modulation of Nociception: Focus on Receptor Multiplicity.- A. General Introduction.- B. Control of Sympathetic and Motor Function at the Segmental Level: Relevance to Pain and Its Modulation.- C. Noradrenaline, Adrenaline and Adrenergic Receptors.- I. Multiple Adrenergic Receptors.- II. Functional Organization of Noradrenergic and Adrenergic Input to the Dorsal Horn.- 1. Origins of Descending Noradrenergic and Adrenergic Pathways.- 2. Influence on Projection Neurones and Interneurones in the Dorsal Horn.- 3. Influence on Primary Afferent Fibres.- III. Descending Noradrenergic Inhibition.- 1. Involvement of Several Medullary Noradrenergic Nuclei.- 2. Functional Modulation.- IV. Pharmacology of Spinal Adrenergic Mechanisms Modulating Nociception.- 1. Experimental Data.- 2. Clinical Data.- 3. Facilitation of the Actions of Local Anaesthetics and Opioids.- V. ?2-AR Subtypes and Antinociception.- 1. Localization of ?2-AR Subtypes in the Dorsal Horn.- 2. Functional Evidence for Multiple ?2-AR Subtypes Modulating Nociception.- D. Serotonin and Serotonin Receptors.- I. Multiple Serotonin Receptors.- II. Functional Organization of Serotoninergic Input to the Dorsal Horn.- 1. Origin of Descending Serotoninergic Pathways.- 2. Influence on Projection Neurones in the Dorsal Horn.- 3. Influence on Interneurones in the Dorsal Horn.- 4. Influence on Primary Afferent Fibres.- III. Descending Serotoninergic Inhibition.- IV. Pharmacology of Spinal Serotoninergic Mechanisms Modulating Nociception.- 1. 5-HT1A Receptors.- 2. 5-HT1B/5-HT1D Receptors.- 3. 5-HT2A/2C Receptors.- 4. 5-HT3 Receptors.- 5. Other 5-HT Receptor Types.- E. General Discussion and Conclusions.- References.- 16 Neonatal Pharmacology of Pain.- A. Introduction.- I. Anatomical Background.- II. Physiological Background.- B. Neonatal Pharmacology of Excitatory Pathways Involved in Pain.- I. Glutamate.- 1. NMDA Receptors.- 2. AMPA Receptors.- 3. Metabotropic Receptors.- II. Neuropeptides.- C. Neonatal Pharmacology of Inhibitory Pathways Involved in Pain.- I. GABA.- II. Opiates.- III. Monoamines.- D. Concluding Comments.- References.