Opioids I

ISBN-13: 9783642774621 / Angielski / Miękka / 2011 / 815 str.

H. Akil;S. Archer;A. Beaumont

Opis

In 1957 Otto SCHAUMANN, one of the pionieers in pharmacological research on morphine and the first to prepare synthetic opiates, presented a mono- graph entitled "Morphin und morphiniihnliche Verbindungen" as Volume 12 of the Handbook of Experimental Pharmacology. Now, 35 years later, we are publishing in the same series a new comprehensive volume covering the present status of opioid research. Since that time the topic has expanded enormously. The identification of opioid receptors and the detection of their endogenous ligands were landmarks which opened a new era in opioid research and fertilized the entire field of neurobiology. The rapid develop- ment of this field is illustrated in the figure, which represents the number of papers published on opioid research since 1970 (searches performed on the MEDLINE data base). 3000 Vl

Spis treści

Section A: Opioid Receptors/Multiplicity.- 1 Opioid Receptor Multiplicity: Isolation, Purification, and Chemical Characterization of Binding Sites.- A. Introduction.- B. Opioid Receptors Exist in Multiple Types.- C. Selective Ligands for the Major Types of Opioid Receptors.- D. Characterization of Membrane-Bound Opioid Receptor Types.- E. Putative Endogenous Ligands.- F. Separation and Purification of Opioid Binding Sites.- I. Solubilization.- II. Physical Separation.- III. Affinity Cross-Linking.- IV. Partial Purification.- V. Purification to Homogeneity.- G. Recent Studies on Purified ?-Opioid Binding Protein.- I. Antibodies Generated Against Peptide Sequences.- II. Rhodopsin Antibodies React with Purified OBP.- III. Attempts to Clone the cDNA of Purified OBP.- H. Concluding Comments.- References.- 2 Expression Cloning of cDNA Encoding a Putative Opioid Receptor.- A. Project History.- B. Expression Cloning.- I. Methodology.- II. Attempt by Stable Transfection.- III. Transient Transfection, Panning.- C. Ligand Binding by the Expressed Receptor.- D. Sequence Analysis, Structure of the Receptor.- E. Conclusions.- References.- 3 Characterization of Opioid-Binding Proteins and Other Molecules Related to Opioid Function.- A. Introduction.- B. cDNA Cloning.- I. Molecular Cloning of OBCAM.- II. Molecular Cloning and Characterization of Gene Products Downregulated by Chronic Opioid Treatment of NG108-15 Cells.- III. Use of Consensus Sequences in cDNA Cloning of Opioid Receptors.- C. Use of Antibodies to Characterize Opioid Receptors.- D. Antisense cDNA.- References.- 4 Use of Organ Systems for Opioid Bioassay.- A. Introduction.- I. Rationale for the Use of Isolated Organ Systems.- II. Tissue Preparations.- III. Applications of Peripheral Tissue Bioassay.- B. Measurement of Pharmacological Constants.- I. Theoretical Considerations.- 1. Determination of Agonist Affinity.- 2. Determination of Antagonist Affinity.- II. Methodological Considerations.- 1. Choise of Tissue Preparation.- 2. Tissue Preparation and Setup.- 3. Optimization of Equilibrium Conditions.- C. Assay Preparations.- I. Guinea Pig Ileum.- 1. ?-Receptors.- 2. ?-Receptors.- 3. ?-Receptors.- II. Mouse Vas Deferens.- 1. ?-Receptors.- 2. ?-Receptors.- 3. ?-Receptors.- III. Other Vasa Deferentia.- 1. Rat Vas Deferens.- 2. Hamster Vas Deferens.- 3. Rabbit Vas Deferens.- D. Conclusions.- References.- 5 Anatomical Distribution of Opioid Receptors in Mammalians: An Overview.- A. Introduction.- B. Anatomical Distributions.- I. ?-Receptors.- II. ?-Receptors.- III. ?-Receptors.- IV. Anatomical Conclusions.- C. Multiple ?-Receptor Subtypes.- D. Nigrostriatal and Mesolimbic Dopamine Systems as Models for Opioid Peptide and Receptor Interactions.- I. Conclusions.- E. Future Directions.- References.- 6 Opioid Receptor Regulation.- A. Introduction.- B. Regulation of Opioid Receptors in the Adult Brain by Chronically Administered Opioid Agonists and Antagonists.- I. Chronic Administration of Opioid Agonists In Vivo.- II. Chronic Administration of Agonists to Cells Grown in Culture.- III. Chronic Administration of Opioid Antagonists.- C. Regulation of Opioid Receptors by Other Drugs or Specific Brain Lesions.- D. Regulation of Opioid Receptor and Peptide Gene Expression in Embryonic and Neonatal Brain.- I. Effects of Chronic Opioid Administration on Opioid Receptor Expression.- 1. Perinatal Treatment.- 2. Postnatal Treatment.- II. Effects of Chronic Opioid Administration on Opioid Peptide Expression.- References.- 7 Multiple Opioid Receptors and Presynaptic Modulation of Neurotransmitter Release in the Brain.- A. Introduction.- B. Modulation of Noradrenaline Release.- C. Modulation of Acetylcholine Release.- D. Modulation of Dopamine Release.- E. Modulation of the Release of Other Neurotransmitters.- F. Conclusions.- References.- 8 Opioid Receptor-G Protein Interactions: Acute and Chronic Effects of Opioids.- A. Introduction.- B. Effects of Guanine Nucleotides on Ligand Binding to Opioid Receptors.- I. Opioid ?- and ?-Receptors Are Funtionally Linked to Guanine Nucleotide Binding Proteins.- 1. Guanine Nucleotides Lower Agnonist Affinity at ?- and ?-Receptors.- 2. Guanine Nucleotides Increase Agonist Dissociation Rates.- 3. Guanine Nucleotide Effects on Equilibrium Binding of Opioids.- 4. Sodium Regulates Agonist Affinity at ?- and ?-Receptors.- 5. Stimulation of GTPase Activity by Activation of ?- and ?-Receptors.- II. Evidence for ?-Receptor Interactions with G Proteins.- 1. Effects of Guanine Nucleotides on Agonist Binding at ?1-Sites.- 2. Effects of Guanine Nucleotides on Binding at ?2-Sites.- III. Stimulatory Effects of Opioids: Possible Interactions of Opioid Receptors with Gs.- C. Cellular Consequences of Sustained Exposure to Opiate Drugs.- I. Characteristics of Opioid Tolerance and Dependence.- II. Changes in the Number of Opioid Receptors Following Sustained Exposure to High Concentrations of Opiate Drugs.- 1. In Vitro Studies Employing Tissue Culture.- 2. Effects of Chronic Opioid Treatment in Brain.- 3. Effects of Chronic Treatment with ?-Agonists.- 4. Mechanisms Implicated in Changes in Receptor Site Density.- III. Chronic Opioid Treatment Uncouples Opioid Receptors from Their Associated G Proteins.- 1. Receptor Desensitization; ?- and ?-Receptors.- 2. Mechanisms Implicated in Receptor Desensitization.- IV. Sustained Opioid Exposure Induces Changes in the Cellular Concentrations of Some G Proteins.- 1. Neuroblastoma X Glioma (NG 108–15) Hybrid Cells.- 2. Guinea Pig Ileum Myenteric Plexus.- 3. Central Nervous System.- 4. Agonist Regulation of G Protein Levels.- V. Effector System Function May Be Enhanced After Sustained Opiate Drug Treatment.- 1. Guinea Pig Ileum Myenteric Plexus.- 2. Neuroblastoma X Glioma (NG 108–15) Hybrid Cells.- 3. Dorsal Root Ganglion-Spinal Cord Cultures.- 4. Locus Ceruleus.- 5. Summary.- VI. Summary: G Proteins and Opioid Tolerance and Dependence.- References.- 9 Opioid Receptor-Coupled Second Messenger Systems.- A. Introduction.- B. G Protein Coupling to Receptors.- I. General G Protein Structure and Function.- II. Opioid Receptors Are Coupled to G Proteins.- C. Opioid-Inhibited Adenylyl Cyclase.- I. Acute Effects of Opioid Agonists on Adenylyl Cyclase in Transformed Cell Lines.- II. Acute Effects of Opioid Agonists on Adenylyl Cyclase in Brain.- III. Chronic Effects of Opioid Agonists.- IV. Biological Roles for Opioid-Inhibited Adenylyl Cyclase.- D. Other Second Messenger Systems.- I. Stimulation of Adenylyl Cyclase.- II. Cyclic GMP.- III. Phosphatidylinositol Turnover and Effects on Membrane Lipids.- IV. Opioid-Dependent Protein Phosphorylation.- E. Conclusions.- References.- 10 Allosteric Coupling Among Opioid Receptors: Evidence for an Opioid Receptor Complex.- A. Introduction.- B. Evidence for a ?-?-Opioid Receptor Complex.- I. Ligand-Binding Data.- 1. Evidence that ?-Ligands Noncompetitively Inhibit ?-Receptor Binding.- 2. Evidence that ?-Ligands Noncompetitively Inhibit ?-Receptor Binding.- II. ?-Agonist — ?-Agonist Interactions.- 1. Early Studies: Analgesia Model.- 2. More Recent Studies: Analgesia Model.- III. ?-Antagonist — ?-Antagonist Interactions.- IV. Linkage Studies.- C. Evidence for a ?-Binding Site Associated with the ?-?-Opioid Receptor Complex.- I. In Vitro, Electrophysiological, Anatomical, and Biochemical Evidence for a ?-?-Opioid Receptor Complex.- D. Conclusions.- References.- Section B: Chemistry of Opioids with Alkaloid Structure.- 11 Chemistry of Nonpeptide Opioids.- A. Introduction.- B. Biosynthesis of Morphine, Codeine, and Thebaine.- C. Morphine and Its Companions.- D. Transformation Products of Thebaine.- E. Morphinans.- F. Diene Adducts Derived from Thebaine.- G. 6, 7-Benzomorphans.- H. Piperidine-Based Opioids.- I. Ethylene Diamines.- J. Acyclic Opioids.- K. Concluding Remarks.- References.- 12 Selective Nonpeptide Opioid Antagonists.- A. Introduction.- B. Receptor Selectivity.- C. ?-Selective Opioid Antagonists.- D. ?-Selective Opioid Antagonists.- E. ?-Selective Opioid Antagonists.- References.- 13 Presence of Endogenous Opiate Alkaloids in Mammalian Tissues.- A. Introduction.- B. Technical Principles Used in the Isolation of Alkaloid Compounds from Animal Tissue.- C. Identification of Endogenous Opiate Alkaloids in Mammalian Tissue.- D. Biosynthesis of Mammalian Morphine.- E. Regulation of Endogenous Morphine and Search for a Physiological Role.- References.- Section C: Opioid Peptides.- 14 Regulation of Opioid Peptide Gene Expression.- A. Introduction.- B. Structure and Regulatory Elements of the Opioid Peptide Genes.- I. Proopiomelanocortin.- II. Proenkephalin.- III. Prodynorphin.- C. Gene Regulation.- I. Proopiomelanocortin.- 1. Adenohypophysis.- 2. Intermediate Pituitary.- 3. Hypothalamus.- 4. Peripheral Tissues.- 5. Tumors.- II. Proenkephalin.- 1. Striatum.- 2. Hypothalamus.- 3. Hippocampus and Cortex.- 4. Spinal Cord and Lower Brainstem.- 5. Pituitary.- 6. Adrenal Medulla.- 7. Heart.- 8. Gonads.- 9. Immune System.- 10. Cell Lines.- III. Prodynorphin.- 1. Hypothalamus.- 2. Striatum.- 3. Hippocampus.- 4. Spinal Cord.- 5. Pituitary.- 6. Peripheral Tissues.- D. Summary.- References.- 15 Regulation of Pituitary Proopiomelanocortin Gene Expression.- A. Introduction.- I. The POMC Gene.- II. Intracellular Processes Regulating POMC Secretion.- B. Proopiomelanocortin mRNA Levels in Pituitary.- I. Whole Animal Studies.- 1. Adrenalectomy.- 2. Hypothalamic Factors.- 3. Intermediate Lobe POMC mRNA Levels.- II. In Vitro Systems.- 1. Glucocorticoids.- 2. cAMP- and Calcium-Dependent Processes.- III. Summary.- C. Proopiomelanocortin Gene Transcription.- I. Modulation of POMC hnRNA Levels.- II. Whole Animal Studies.- III. Primary and AtT20 Cell Culture.- IV. Summary.- D. Regulatory Elements in the POMC Gene.- I. Basal and Tissue-Specific Promoter Elements.- II. Glucocorticoid Regulatory Elements.- III. Promoter Elements and Second Messenger Pathways.- IV. Summary.- E. Conclusions.- References.- 16 Molecular Mechanisms in Proenkephalin Gene Regulation.- A. Introduction.- B. Cellular Signaling Pathways Mediating PENK Gene Induction.- I. Membrane Associated Events and Second Messengers.- 1. Regulation of PENK Gene Expression by Electrical Activity and Ca2+ Metabolism in Excitable Cells.- 2. Cyclic AMP as a Regulator of PENK Gene Expression.- 3. Phosphoinositide Hydrolysis and PENK Gene Regulation.- II. Regulation of PENK Gene Expression by Third Messengers.- C. Mechanisms of PENK Gene Transcriptional Regulation.- I. Transcriptional Regulation of the Endogenous PENK Gene.- II. Gene Transfer Approach.- III. DNA-Responsive Elements.- D. Summary.- References.- 17 Proopiomelanocortin Biosynthesis, Processing and Secretion: Functional Implications.- A. Introduction.- B. Tissue-Specific Processing.- I. Anterior Lobe.- II. Intermediate Lobe.- III. Brain.- C. Proopiomelanocortin Processing and Modifying Enzymes.- D. Possible Functional Significance of Posttranslational Modifications to POMC-Derived Peptides.- I. Anterior Lobe.- II. Intermediate Lobe.- III. Brain.- 1. Central Analgesia, Tolerance and Dependence.- 2. Reinforcement.- 3. Autonomic Functions.- IV. Immune System.- E. Conclusion.- References.- 18 Biosynthesis of Enkephalins and Proenkephalin-Derived Peptides.- A. Introduction.- B. History.- C. Enkephalin Biosynthesis in the Adrenal Medulla.- D. Molecular Biology.- E. Enkephalin Biosynthesis in the CNS.- F. Synenkephalin.- G. Molecular Evolution of Proenkephalin.- H. Extraneuronal Proenkephalin.- I. Reproductive Tissue.- II. Glial Cells.- III. Immune System.- I. Processing of Proenkephalin.- J. Regulation.- K. Conclusion.- References.- 19 Prodynorphin Biosynthesis and Posttranslational Processing.- A. History of Dynorphin.- B. Posttranslational Processing Signals.- C. Prodynorphin Biosynthesis and Processing in Peripheral Tissues.- D. Processing Pathway of Prodynorphin.- E. Functional Significance of Prodynorphin Peptide Processing.- I. Striatonigral System.- II. Other Systems.- F. Conclusions.- References.- 20 Anatomy and Function of the Endogenous Opioid Systems.- A. Introduction.- B. Immunocytochemical Anatomy of Opioid Systems.- I. Proopiomelanocortin.- II. Proenkephalin.- III. Prodynorphin.- C. In Situ Hybridization Histochemical Studies.- I. Proopiomelanocortin mRNA.- II. Proenkephalin and Prodynorphin mRNA.- III. Expression of Opioids in Nonneuronal Cells.- D. Opioid Receptors and Functional Systems.- I. Problems in the Functional Analysis of Endogenous Opioid Systems.- II. Opioid Peptide-Receptor Relationships.- E. Functional Roles of Opioid Systems.- I. Endogenous Pain Control Systems.- II. Extrapyramidal Motor Systems.- References.- 21 Atypical Opioid Peptides.- A. Introduction.- I. Atypical Representatives of Natural Opioid Peptides (Atypical Natural Opioid Peptides).- II. Peptides with Indirect Opioid or Opioid Antagonist Activity.- B. Atypical Opioid Peptides.- I. Structure and Activity.- 1. ?-Casein Exorphins.- 2. ?-Casomorphins.- 3. ?-Casorphin, ?- and ?-Lactorphins.- 4. Hemorphins and Cytochrophins.- 5. Dermorphins and Deltorphins.- II. Origin and Destination.- 1. Milk Protein-Derived Opioid Peptides.- 2. Hemoglobin- or Cytochrome b-Derived Opioid Peptides.- 3. Amphibian Skin Protein-Derived Opioid Peptides.- C. Opioid Antagonists Sharing Characteristics with Atypical Opioid Peptides.- I. Structure and Activity.- 1. Casoxins.- 2. Lactoferroxins.- II. Origin and Destination.- D. Atypical Opioid Peptide Analogues with Agonist or Antagonist Activity.- I. Agonists.- 1. ?-Selective Opioid Receptor Ligands.- 2. ?-Selective Opioid Receptor Ligands.- II. Antagonists.- E. Concluding Remarks.- References.- 22 Opioid Peptide Processing Enzymes.- A. Introduction.- B. Enzymes in the Endoplasmic Reticulum and Golgi Apparatus.- I. Signal Peptidase.- II. Glycosylation, Sulfation, and Phosphorylation.- C. Enzymes in the Secretory Granules.- I. Endopeptidases Selective for Paired Basic Residues.- II. Opioid Peptide Processing Endopeptidases Selective for Single Basic Residues.- III. Carboxypeptidase E.- IV. Aminopeptidase B-Like Enzyme.- V. Amidation.- VI. Acetylation.- D. Extracellular Opioid Peptide Processing Enzymes.- References.- 23 Peptidase Inactivation of Enkephalins: Design of Inhibitors and Biochemical, Pharmacological and Clinical Applications.- A. Introduction.- B. Enkephalin Degrading Enzymes.- I. Metabolism of Opioid Peptides.- II. Substrate Specificity of NEP and APN.- III. Assays of NEP and APN Activities.- C. Structure and Molecular Biology of NEP.- I. Structure of NEP.- II. Human NEP (CALLA) Gene.- D. Localization of Neutral Endopeptidase 24.11.- I. Central Nervous System.- II. Localization of NEP in Peripheral Tissues.- III. In Vitro and In Vivo Studies of Enkephalin Degradation by NEP and APN.- E. Inhibitor Design and Synthesis.- I. Design of Selective and Mixed Inhibitors of Neutral Endopeptidase 24.11 and Aminopeptidase N.- II. Thiol Inhibitors.- III. Carboxyl Inhibitors.- IV. Hydroxamic Acids and Derivatives.- V. Phosphorus-Containing Inhibitors.- VI. Aminopeptidase-N and Dipeptidyl Peptidase Inhibitors.- VII. Development of Mixed Inhibitors of Enkephalin-Degrading Enzymes.- F. Pharmacological Studies of Enkephalin-Degrading-Enzyme Inhibitors.- I. Inhibitor-Induced Analgesia.- II. Inhibitor-Induced Spinal Antinociception.- III. Peptidase Inhibitors in Chronic Pain.- IV. Tolerance, Dependence, and Side Effects of Selective and Mixed Inhibitors of NEP and APN.- V. Gastrointestinal Effects.- VI. Role of Neutral Endopeptidase-24.11 in Airways.- VII. Behavioral Effects of Inhibitors.- G. Inhibition of NEP Inactivation of Atrial Natriuretic Peptide: Pharmacological and Clinical Implications.- H. Clinical Applications of Selective and Mixed Zn Metallopeptidase Inhibitors.- References.- 24 Coexistence of Opioid Peptides with Other Neurotransmitters.- A. Principles.- I. Introduction.- II. Subcellular Features.- 1. Classical Neurotransmitters and Small Synaptic Vesicles.- 2. Neuropeptides and Large Granular Vesicles.- III. Methods for Establishing Coexistence.- B. Coexistence Within Areas of the Nervous System.- I. Retina.- II. Telencephalon.- III. Diencephalon.- IV. Mesencephalon.- V. Pons and Medulla.- VI. Cerebellum.- VII. Spinal Cord.- VIII. Peripheral Nervous System.- 1. Primary Afferent Neurons.- 2. Autonomic Ganglion Cells and Their Fibers.- 3. Adrenal Medulla.- 4. Enteric Nervous System.- C. Implications.- I. Patterns of Expression.- II. Pharmacology and Physiology.- References.- 25 Interrelationships of Opioid, Dopaminergic, Cholinergic and GABAergic Pathways in the Central Nervous System.- A. Introduction.- B. Cholinergic Systems.- I. Introduction.- II. Septohippocampal Cholinergic Pathway.- III. Nucleus Basalis-Cortical Cholinergic Pathway.- C. Dopaminergic Pathways.- I. Introduction.- II. Nigrostriatal Pathway.- III. Mesolimbic Pathways.- IV. Mesocortical Pathways.- D. GABAergic Pathways.- E. Striatal Opioid Peptide Gene Expression.- I. Introduction.- II. Met- Enkephalin.- III. Dynorphin.- F. Conclusions.- References.- 26 Selectivity of Ligands for Opioid Receptors.- A. Introduction.- B. Methods Used to Determine the Selectivity of Opioid Compounds.- I. Radioreceptor Binding Assays.- II. Bioassays.- C. Selectivity of Endogenous Opioid Peptides.- I. Proenkephalin-Derived Peptides.- 1. Activity in Binding Assays.- 2. Activity in Bioassays.- II. Prodynorphin-Derived Peptides.- 1. Activity in Binding Assays.- 2. Activity in Bioassays.- III. Proopiomelanocortin-Derived Peptides.- 1. Activity in Binding Assays.- 2. Activity in Bioassays.- IV. Dermorphin and Deltorphins.- 1. Activity in Binding Assays.- 2. Activity in Bioassays.- D. Selectivity of Nonendogenous Opioid Compounds.- I. Compounds with a Preference for the ?-Binding Site.- 1. Activity in Binding Assays.- 2. Agonist Activity in Bioassays.- 3. Antagonist Activity in Bioassays.- II. Compounds with a Preference for the ?-Binding Site.- 1. Activity in Binding Assays.- 2. Agonist Activity in Bioassays.- 3. Antagonist Activity in Bioassays.- III. Compounds with a Preference for the ?-Binding Site.- 1. Activity in Binding Assays.- 2. Agonist Activity in Bioassays.- 3. Antagonist Activity in Bioassays.- References.- 27 Development of Receptor-Selective Opioid Peptide Analogs as Pharmacologic Tools and as Potential Drugs.- A. Introduction.- B. Determination of Receptor Selectivity.- C. Development of ?-, ?-, and ?-Receptor-Selective Opioid Peptide Analogs with Agonist Properties.- I. ?-Selective Agonists.- 1. Linear Opioid Peptide Analogs.- 2. Opioid Peptide Dimers.- 3. Cyclic Opioid Peptide Analogs.- II. ?-Selective Agonists.- 1. Linear Opioid Peptide Analogs.- 2. Opioid Peptide Dimers.- 3. Cyclic Opioid Peptide Analogs.- III. ?-Selective Agonists.- D. Selective Opioid Peptide Analogs with Antagonist Properties.- E. Irreversible Opioid Receptor Peptide Ligands.- I. Chemical Affinity Labels.- II. Photoaffinity Labels.- F. Selective Opioid Peptide Analogs as Drug Candidates.- G. Conclusions.- References.- 28 Ontogeny of Mammalian Opioid Systems.- A. Introduction.- B. Embryological Considerations.- C. Opioid Gene Activation.- I. Proopiomelanocortin.- 1. Brain.- 2. Pituitary.- 3. Testis.- 4. Placenta.- II. Enkephalin.- 1. Brain (Striatal).- 2. Glia.- 3. Fetal Mesoderm.- III. Dynorphin.- D. Ontogeny of Opioid Precursor Processing.- I. Proopiomelanocortin.- 1. Immunocytochemical Analyses.- 2. Biochemical Analyses.- II. Dynorphin.- E. Ontogeny of Regulated Release.- I. Secretory Granules, Regulators of POMC Secretion and the Portal System.- II. Functional Receptors for Secretagogues.- F. Function.- I. Ontogeny of Opioid Receptors.- II. Putative Role(s) of Opioid Peptides in Developmental Processes.- G. Prospectus.- References.- Section D: Neurophysiology.- 29 Opioids and Sensory Processing in the Central Nervous System.- A. Introduction.- B. Opioids and the Spinal Cord.- I. Spinal Processing of Nociceptive Information.- II. Systemic Administration of Opiates and the Responses of Spinal Neurones.- 1. Neuronal Types.- 2. Responses to Peripheral Stimuli.- III. Localized Administration of Opioids.- 1. ?-Receptor-Preferring Ligands.- 2. ?-Receptor-Preferring Ligands.- 3. ?-Receptor-Preferring Ligands.- IV. Functional Consequences of Opioid Receptor Activation to Spinal Sensory Processing.- 1. Opioid Receptors and the Central Terminals of Nociceptors.- 2. Receptors on the Somata and Processes of Spinal Neurones.- 3. Receptors and Supraspinal Fibres.- V. Opiates and Descending Inhibition.- VI. Physiological Roles of Opioid Peptides in Sensory Processing.- 1. Spinal Release of Opioid Peptides.- 2. Tonic Opioidergic Inhibition.- 3. Phasic Opioidergic Inhibition.- C. Thalamus and Cerebral Cortex.- I. Thalamus.- 1. Ventrobasal Nuclei.- 2. Medial and Dorsal Thalamic Nuclei.- II. Cerebral Cortex.- D. Deficits in Knowledge and Prospects for Future Research.- References.- 30 Opioid Actions on Membrane Ion Channels.- A. Introduction.- B. Calcium Channels.- I. Types of Calcium Channels.- II. ?-Receptors.- III. ?-Receptors.- IV. ?-Receptors.- V. Unclassified Receptors.- VI. Experiments on Action Potential Duration.- VII. Type of Calcium Current Inhibited.- VIII. Mechanism of Opioid Action.- 1. Role of G Proteins.- 2. Time Course of Agonist Action.- 3. Single Channel Studies.- 4. Voltage Dependence of Agonist Action?.- IX. Other Receptors That Reduce Calcium Currents.- X. Calcium Current Inhibition and Presynaptic Inhibition.- C. Potassium Channels.- I. Types of Potassium Channels.- II. ?-Receptors.- III. ?-Receptors.- IV. Other Receptors.- V. Experiments on Action Potential Duration.- VI. Hyperpolarization and Inhibition of Firing.- VII. Type of Potassium Current Increased.- VIII. Mechanism of Opioid Action.- 1. Role of G Proteins.- 2. Time Course of Action.- 3. Single Channel Studies.- IX. Other Receptors That Increase Potassium Conductance.- X. Potassium Conductance Increase and Presynaptic Inhibition.- D. Other Ion Channels.- E. Changes in Tolerance and Dependence.- F. Concluding Remarks.- References.