The Pharmacology of Pain

ISBN-13: 9783642645501 / Angielski / Miękka / 2011 / 479 str.

A. Dickenson; J. -M Besson

Opis

Pain is a symptom of many clinical disorders, afflicts a large proportion of the population and is largely treated by pharmacological means. However, the two main classes of drugs used are the opioids and the non-steroidal anti- inflammatory drugs, drugs that have a long history. The last decade has seen remarkable advances in our understanding of some of the pharmacological bases of pain and analgesia and this book aims to reflect these rapid changes in our understanding of pain mechanisms. One impetus to these scientific advances has been dialogue and interactions between scientists and clinicians; as a result we now has a number of animal models of clinical pain states, to mimic certain aspects of clinical pathophysiological pain states. Molecular aspects of receptors and the synthesis of tools for probing receptor function have also been rapid growth areas. A number of controlled clinical studies using novel licensed drugs have also resulted from recent research, offering hope to certain patients with severe intractable pain. However, we desperately need the pharmaceutical industry to develop new drugs based on these novel targets for analgesic therapy. This book attempts to provide an overview of the important areas of the pharmacology of pain. This book, although providing an account of the pharmacology of pain transmission and its control based on the underlying anatomical organization and physiological responses, does not attempt to cover these latter two areas.

Spis treści

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.