Opioids I

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.