Opiate Receptor Subtypes and Brain Function U. S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration Opiate Receptor Subtypes and Brain Function Editors: Roger M. Brown, Ph.D. Doris H. Clouet, Ph.D. David P. Friedman, Ph.D. Neuroscience Branch Division of Preclinical Research National Institute on Drug Abuse NIDA Research Monograph 71 1986 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, Maryland 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, DC 20402 NIDA Research Monographs are prepared by the research divisions of the National lnstitute on Drug Abuse and published by its Office of Science The primary objective of the series IS to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, and Integrative research reviews. Its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community Editorial Advisors MARTIN W. ADLER, Ph.D. SIDNEY COHEN, M.D. Temple University School of Medicine Los Angeles, California Philadelphia, Pennsylvania SYDNEY ARCHER, Ph.D. MARY L. JACOBSON Rensselaer Polytechnic: lnstitute National Federaiton of Parents for Troy, New York Drug Free Youth RICHARD E. BELLEVILLE, Ph.D. Omaha. Nebraska NB Associates, Health Sciences Rockville, Maryland REESE T. JONES, M.D. KARST J. BESTEMAN Langley Porter Neuropsychiatric Institute San Francisco, CalIfornia Alcohol and Drug Problems Association of North America Washington, D.C. DENISE KANDEL, Ph.D. GILBERT J. BOTVIN, Ph.D. College of Physicians and Surgeons of Cornell University Medical College Columbia University New York, New York New York, New York JOSEPH V. BRADY, Ph.D. The Johns Hopkins University School of HERBERT KLEBER, M.D. Medicine Yale University School of Medicine Baltimore, Maryland New Haven, Connecticut THEODORE J. CICERO, Ph.D. Washington University School of RICHARD RUSSO Medicine New Jersey State Department of Health St Louis, Missouri Trenton, New Jersey NIDA Research Monograph Series CHARLES R. SCHUSTER, Ph.D. Director, NIDA JEAN PAUL SMITH, Ph.D. Acting Associate Director for Science, NIDA Acting Editor Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857 Opiate Receptor Subtypes and Brain Function ACKNOWLEDGMENT This monograph is based upon papers and discussion from a technical review on opiate receptor subtypes and brain function which took place on September 26 and 27, 1985, at Bethesda, Maryland. The review meeting was sponsored by the Office of Science and the Division of Preclinical Research, National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder's permission is required. All other material in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of the source is appreciated. The U. S. Government does not endorse or favor any specific commercial product or commodity. Trade names appearing in this publication are used only because they are considered essential in the context of the studies reported herein. DHHS publication number (ADM)86-1462 Printed 1986 NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of American Statistics Index, Biosciences Information Service, Chemical Abstracts, Current Contents, Psychological Abstracts, and Psychopharmacology Abstracts. iv Contents Page Preface . vii Properties of Receptors Mediating Opioid Effects: Discrimination of Receptor Types Brian M. Cox and Charles Chavkin . 1 Dynorphin: Specific Binding to Opiate Receptors Nancy M. Lee and Herbert Lundahl . 19 Selective Radioligands for Characterization and Neuroanatomical Distribution Studies of Brain Opioid Receptors R. Suzanne Zukin, Ann Tempel, and Mahboubeh Eghbali........28 Anatomical and Biochemical Perspectives on Opioid Peptides Robert P. Elde ............................................. 48 Opiate-Inhibited Adenylate Cyclase in Mammalian Brain Membranes Steven R. Childers, Peter Nijssen, Pautine Nadeau, Page Buckhanna, Phi-Van Le, and Jeffrey Harris........65 Membrane Conductances and Opioid Receptor Subtypes R. Alan North .............................................. 81 Modulation of Opioid Peptide Metabolism by Seizures: Differentiation of Opioid Subclasses Jacqueline F. McGinty, Tomoyuki Kanamatsu, Johnny Obie, and Jau-Shyong Hong ........................................ 89 Kappa Isoreceptors: Neuroendocrine and Neurochemical Evidence Paul L. Wood and Smriti Iyengar . 102. v Page Multiple Receptor Types in Opioid Discrimination Stephen G. Holtzman . 109 Neurobiological Substrates of Drug Self-Administration Jamee E. Smith and Steven I. Dworkin . 127 Neurochemical Substrates for Opiate Reinforcement George P. Koob, Franco J. Vaccarino, Marianne Amalric, and Floyd E. Bloom . 146 Opiate Receptor Subtypes Associated With the Brain Mechanisms of Feeding and Reward Roy A. Wise, Francois Jenck, Alain Gratton, and Remi Quirion . 165 In Vivo Interactions Among Opiate Receptor Agonists and Antagonists John W. Holaday, Frank C. Tortella,, Rhoda Maneckjee, and Joseph B. Long . 173 List of NIDA Research Monographs . 189 vi Preface OPIOID RECEPTOR SUBTYPES AND BRAIN FUNCTIDN A technical review was held on September 26 and 27, 1985, at the National Institute on Drug Abuse to examine the current state of knowledge of opiate receptor subtypes and specific opioid peptides that act on these receptor subtypes, and to consider how brain function might be related to the diversity of receptor/ligand combinations. This monograph consists of papers delivered at this review. The conclusion of each presentation, suggested or ex- pressed, was that there are indeed a variety of opioid receptors differing in ligand specificity and location in the nervous system, and that these receptors do mediate different functions. The current descriptions of the complex processes underlying the functioning of opioid neuronal pathways have been derived from investigations at all levels from the molecular to the behav- ioral. It now appears that by combining new neuroscience technol- ogy with well-described behavioral paradigms, questions about the effects of the various peptide-ligands and receptors on behavior itself can be answered. As a group, the papers reveal the wide- spread distribution and influence of opiopeptides within the nerv- ous system and highlight some of the exquisitely sensitive control mechanisms that allow these systems to react to and counteract the varieties of influences that make up our daily lives as well as those of drug abusers. Multiple Receptor Subtypes Defined The uses of the various methods that serve to define opioid recep- tors and pitfalls of these methods were described by BRIAN COX. The original definition of subtypes termed the mu, kappa, and sigma receptors was based on physiological responses to opiates in the chronic spinal dog. More recently, two new subtypes, delta and epsilon receptors, have been recognized as well. Newer metho- dologies for characterizing receptors have utilized biochemical measures of binding affinities (KD), total numbers of receptors (Bmax), potencies of various agonists (A50 and IC50), agonist affinities as measured from agonist effects? (KA), and estimates of vii antagonist affinity (Ke). Although a few of the endogenous opioid ligands may have exquisite specificity for some subtypes of the opiate receptor, the synthetic narcotic agonists and antagonists and the opiopeptide-related synthetic compounds generally react with more than one subtype of opiate receptor. Although the specificity of synthetic ligands continues to improve, cross- reactivity makes the determination of the physical characteristics of the receptors difficult. Many neuropeptide hormones exist as large molecules, sometimes active, that can be hydrolyzed by peptidase action into smaller peptides that are active harmonally. Proopiomelanocortin is such a peptide. It is processed into several active subunits including beta-endorphin. In turn, beta-endorphin is hydrolyzed into smaller subunits including methionine-enkephalin. Dynorphin is another opiopeptide that can be hydrolized into smaller active peptides. NANCY LEE described this process, showing that short peptides tended to react with mu and delta receptors, while longer segments reacted at kappa receptors. Using refined methodology, she showed that none of the dynorphin subunits seem to have a clear specificity for any one receptor subtype. SUZANNE ZUKIN summarized our knowledge of opioid receptor subtypes (table 1), opioid receptor subtype distribution in brain, and lig- and specificities. In addition to biochemically defined receptor properties, the dynamic nature of the receptors is emphasized; they can change in number or affinity depending on the physiolog- ical state or previous drug history. An example of receptor dynamics is "up-regulation" in response to opiate antagonist administration. Treatment with an opiate antagonist such as