Progress in Opioid Research Proceedings of the 1986 International Narcotics Research Conference Editors: John W. Holaday, Ph.D. Ping-Yee Law, Ph.D. Albert Herz, M.D. NIDA Research Monograph 75 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse Office of Science 5600 Fishers Lane Rockville, Maryland 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, DC 20402 172-683 O – 87 – 1 : QL 3 NIDA Research Monographs are prepared by the research divisions of the National Institute 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 Institute National Federation of Parents for Troy, New York Drug-Free Youth RICHARD E. BELLEVILLE, Ph.D. Omaha, Nebraska NB Associates, Health Sciences Rockvllle, Maryland REESE T. JONES, M.D. KARST J. BESTEMAN Langley Porter Neuropsychiatric Institute Alcohol and Drug Problems Association San Francisco, California 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 Umversity 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 Progress in Opioid Research ACKNOWLEDGMENT This monograph is based upon papers from the 1986 International Narcotics Research Conference, held on July 6-11, 1986, in San Francisco, California. In the interest of rapid dissemination, it is published in the NIDA Research Monograph series as reviewed and submitted by the editors, whose names and affiliations follow. JOHN W. HOLADAY, Ph.D. Chief, Neuropharmacology Branch Department of Medical Neurosciences Division of Neuropsychiatry Walter Reed Army Institute of Research Washington, D.C. 20307-5100, U.S.A. PING-YEE LAW, Ph.D. Associate Research Pharmacologist Department of Psychiatry Langley Porter Psychiatric Institute University of California San Francisco, California 94143, U.S.A. ALBERT HERZ, M.D. Director, Department of Neuropharmacology Max Planck Institut für Psychiatrie D-8033 Martinsried, F.R.G. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse or any other part of the U.S. Department of Health and Human Services. The U. S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company 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)87-1507 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 FOREWORD The National Institute on Drug Abuse (NIDA) is pleased to publish Progress in Opioid Research, 1986, the proceedings of the 17th annual scientific meeting of the International Narcotic Research Conference (INRC). This meeting was held in San Francisco in July 1986. The INRC is a unique international organization seeking to develop a fundamental understanding of the basic mechanisms of action of opioids, opioid peptides, and their receptors, research supported in large part by NIDA. This group and its meetings are different from others in the field because a definite effort is made to have young as well as senior investigators attend and present data and results of current, ongoing studies. For instance, in recent years, 75 per cent of the travel funds provided by the Division of Preclinical Research of NIDA for attendance at the meeting have been allocated to young investigators involved in laboratory research on opioids or related subjects. As is true for many other fields, excellence attracts more participants every year and this publication is the largest of any INRC Proceedings, with 155 papers and 113 abstracts included. The trio of editors worked swiftly and vigorously to review and assemble this compendium for publication by NIDA. We are sure that this significant "state-of-the-art" volume of the latest research on the basic mechanisms of drug abuse will be of great value to members of the scientific community and other readers interested in the prevention and treatment of substance abuse. Monique C. Braude, Ph.D. Division of Preclinical Research National Institute on Drug Abuse v PREFACE From our "bay view" in South San Francisco, we witnessed the recent developments in opioid research and reflected on the many notable scientific revelations from prior meetings of the INRC. Historically, the thrust of opioid research has progressed from classic in vivo and in vitro pharmacology toward a molecular description of events at a cellular and sub-cellular level. The 1966 Meeting of the INRC has provided us with an opportunity to view the cutting edge of research defining opioid ligands, receptors, and their functional consequences. In many ways, the opiates have been at the forefront of scientific advances which were subsequently applied to other areas of biochemical, pharmacological, physiological and behavioral research. For example, the early definition of opiate receptors in 1973 has resulted in experimental strategies which have been directly applied to many other endogenous receptor systems. Clearly, the initial description of endogenous peptide ligands for opioid receptors in 1975 provided the major impetus for research in the neurobiology of many other opioid and non-opioid peptides. Likewise, the current emphasis on molecular biology as a means by which to define the biosynthesis and metabolism of endogenous opioids has obvious pertinence to other biologically active peptides. The complex biochemical procedures that have been developed to isolate and purify opiate receptors are already being applied to other receptor systems. Finally, the experimental strategies used to define the functional effects of endogenous opioids have resulted in a further understanding of the interactions between opioid and non-opioid systems. Once again, this year’s International Narcotics Research Conference provided a stimulating environment for the exchange of the most recent advances in opioid research. The program not only reflected many outstanding voluntary papers, but also included four invitational symposia and plenary lectures by international luminaries in pharmacology and the neurosciences. It was the intent of the program committee, under the leadership of Drs. Horace Loh and Nancy Lee, to utilize the plenary lectures as a means by which to acquaint opioid researchers with recent advances in related non-opioid fields. The first plenary lecturer, Dr. Daniel Koshland, discussed bacterial chemotaxis as a model sensory system. Dr. Julius Axelrod presented an update on the transduction of receptor mediated signals and the release of adrenocorticotropin. CTP binding proteins in signal transduction was the topic of the lecture by Dr. John Northrup, and Dr. 5. Numa provided the final plenary lecture on a molecular approach to the function of ionic channels. These outstanding presentations provided a refreshing break from the tachyphylactic effects of continued "opioid exposure", and also fostered new ideas and perspectives with pertinence to opioid research. Unfortunately, despite the tireless efforts of many of our participants, the structures of isolated, purified opiate receptors were not available for presentation at this conference. Additionally, the fundamental problems of tolerance and physical dependence were only minimally addressed. Hopefully, future meetings of the INRC will provide a forum to reveal these advances as prior meetings have served to define the many advances described above. vii Immediately following the INRC Meetings, the editorial board met for two days to review the papers and organize the monograph. In organizing this volume, it was our intention to provide a flowing framework, with related areas presented in logical groupings. We have attempted to arrange the papers into chapters which progress sequentially from biochemical studies of receptors and ligands through morphological descriptions of their localization to the final chapters defining the functional effects of opioid systems. Following the manuscripts, we have included the abstracts that were not submitted as papers. As editors of this volume and participants in this year’s meetings,