Handbook of Experimental Pharmacology

Volume 1041/

Editorial Board

G.V.R. Born, London P. Cuatrecasas, Ann Arbor, MI H. Herken. Berlin

Opioids I Contributors

H. Akil, S. Archer, A. Beaumont, M. Blum, D. Bronstein, S.R. Childers A.D. Corbett, B.M. Cox, V. Dauge, R. Day, S. Dermer, J. Donnerer A.W. Duggan, R. Elde, S.M. Fleetwood-Walker, L.D. Fricker M.-C. Fournie-Zaluski, T.L. Gioannini, A. Goldstein, T. H6kfelt V. H6llt, J.W. Holaday, H. Khachaturian, N. Kley, C.M. Knapp H.W. Kosteriitz, N.M. Lee, F.M. Leslie, N. Levin, M.E. Lewis J.P. Loeffler, H.H. Loh, D. Lorang, J.R. Lundblad, A. Mansour A.H. Mulder, R.A. North, S.J. Paterson, D.E. Pellegrini-Giampietro J.E. Pintar, F. Porreca, P.S. Portoghese, J.L. Roberts, B.R. Roques J. Rossier, R.B. Rothman, M.K.H. Schafer, P.W. Schiller A.N.M. Schoffelmeer, R.E.M. Scott, E.J. Simon, A.P. Smith J.A.M. Smith, S. Spector, A. Tempel, H. Teschemacher, K.A. Trujillo E. Young, S.J. Watson, P.L. Wood, R.S. Zukin

Editor: Albert Herz

Section Editors: H. Akil and E.1. Simon

Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest

Professor Dr.med. ALBERT HERZ Max-Planck-Institut fur Psychiatrie Abteilung Neuropharmakologie Am Klopferspitz 18 W-8033 Martinsried, FRG

Section Editors

Dr. med. HUDA AKIL Mental Health Research Institute School of Medicine University of Michigan 205 Zina Pitcher Ann Arbor, MI 48109, USA

Dr. med. ERIC J. SIMON New York University Medical Center School of Medicine 550 First A venue New York, NY 10016, USA

With 74 Figures and 52 Tables

ISBN -13: 978-3-642-77462-1 e- ISBN -13: 978-3-642-77460-7 DOl: 10.1007/978-3-642-77460-7

Library of Congress Cataloging-in-Publication Data. Opioids I / contributors, H. Akil ... [et al.l; editor, Albert Herz; (H. Akil and EJ. Simon, section editors). p. cm. - (Handbook of experimental pharmacology; v. 104) Includes bibliographical references and index. ISBN-13:978-3-{i42-77462-1 l. Opioids. 2. Opioids - Receptors. I. Akil, H. (Huda) II. Herz, Albert, 1921- . III. Simon, Eric 1. IV. Title: Opioids l. V. Series. [DNLM: 1. Endorphins. 2. Receptors, Endorphin. WI HA51L v. 104 / QU 68 0603] QP905.H3 vol. 104 [RM328] 615' .1 s - dc20 [615' .78] DNLMIDLC for Library of Congress 92-2325 CIP

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List of Contributors

AKIL, H., Mental Health Research Institute, School of Medicine, University of Michigan, 205 Zina Pitcher, Ann Arbor, MI 48109, USA

ARCHER, S., Department of Chemistry, Cogswell Laboratory, Rensselaer Polytechnic Institute, Troy, NY 12180-3590, USA

BEAUMONT, A., Departement de Chimie Organique, U 266 INSERM, UA 498 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, 4, avenue de l'Observatoire, F-75006 Paris, France

BLUM, M., The Fishberg Research Center in Neurobiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

BRONSTEIN, D., Laboratory of Molecular Integrative Neuroscience, National Institute of Environmental Health Sciences, Research Triangle, Park, NC 27709, USA

CHILDERS, S.R., Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083, USA

CORBETT, A.D., Department of Biomedical Sciences, University of Aberdeen, Marischal College, Aberdeen AB9 lAS, Great Britain

Cox, B.M., Department of Pharmacology, Uniformed Services University of the Health Sciences, 4301 lones Bridge Road, Bethesda, MD 20814-4799, USA

DAUGE, V., Departement de Chimie Organique, U 266 INSERM, UA 498 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, 4, avenue de l'Observatoire, F-75006 Paris, France

DAY, R., I.A. DeSeve Laboratory of Biochemical and Molecular Neuro­endocrinology, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W lR7

DERMER, S., The Fishberg Research Center in Neurobiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

VI List of Contributors

DONNERER, J., Department of Experimental and Clinical Pharmacology, University of Graz, A-801O Graz, Austria

DUGGAN, A.W., Department of Preclinical Veterinary Sciences, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, Great Britain

ELDE, R., University of Minnesota, Department of Cell Biology and Neuroanatomy, 321 Church Street SE, Minneapolis, MN 55455, USA

FLEETWOOD-WALKER, S.M., Department of Preclinical Veterinary Sciences, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, Great Britain

FRICKER, L.D., Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA

FOURNIE-ZALUSKI, M.-C., Departement de Chimie Organique, U 266 INSERM, UA 498 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, 4, avenue de l'Observatoire, F-75006 Paris, France

GIOANNINI, T.L., Department of Psychiatry, New York University Medical Center, 550 First Avenue, New York, NY 10016, and Baruch College, CUNY, New York, NY 10010, USA

GOLDSTEIN, AVRAM, Stanford University, 735 Dolores, Stanford, CA 94305, USA

HOKFELT, T., Karolinska Institute, Department of Histology and Neuro­biology, P.O. Box 60 400, S-104 01 Stockholm, Sweden

HOLLT, V., Physiologisches Institut, Universitat Munchen, PettenkoferstraBe 12, W-8000 Munchen, FRG

HOLADAY, J.W., Medicis Corporation, 100 East 42nd Street, 15th Floor, New York, NY 10017, USA

KHACHATURIAN, H., Molecular and Cellular Neuroscience Research Branch, National Institute of Mental Health, Room llC-05, Parklawn Building, Rockville, MD 20857, USA

KLEY, N., Molecular Neurooncology Laboratory, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129-9142, USA

KNAPP, C.M., Department of Pharmacy, Veterans Admin. Hospital, 130 W. Kingsbridge Road, Bronx, NY 10468, USA

KOSTERLITZ, H.W., Unit for Research on Addictive Drugs, Marischal College, University of Aberdeen, Aberdeen AB9 lAS, Great Britain

List of Contributors VII

LEE, N.M., Department of Pharmacology, University of Minnesota Twin Cities, Medical School, 3-249 Millard Hall, 435 Delaware Street, S.E., Minneapolis, MN 55455, USA

LESLIE, F.M., Department of Pharmacology, California College of Medicine, University of California, Irvine, CA 92717, USA

LEVIN, N., The Fishberg Research Center in Neurobiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

LEWIS, M.E., Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA

LOEFFLER, J.P., Laboratoire de Physiologie Generale, IPCB, 21, rue Rene Descartes, F-67100 Strasbourg Cedex, France

LOH, H.H., Department of Pharmacology, University of Minnesota Twin Cities, Medical School, 3-249 Millard Hall, 435 Delaware Street, S.E., Minneapolis, MN 55455, USA

LORANG, D., The Fishberg Research Center in Neurobiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

LUNDBLAD, J.R., The Fishberg Research Center in Neurobiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

MANSOUR, A., Mental Health Research Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720, USA

MULDER, A.H., Department of Pharmacology, Free University Medical Faculty, Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands

NORTH, R.A., Vollum Institute, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA

PATERSON, S.J., U.M.D.S., Guy's and St. Thomas's Medical and Dental School, Department of Pharmacology, Lambeth Palace Road, London SE1 7EH, Great Britain

PELLEGRINI-GIAMPIETRO, D.E., Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461-1988, USA

PINTAR, J.E., Department of Anatomy and Cell Biology, Columbia College of Physicians and Surgeons, 630 W. 168th Street, New York, NY 10032, USA

VIII List of Contributors

PORRECA, F., Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA

PORTOGHESE, P.S., Department of Medicinal Chemistry, College of Phar­macy, University of Minnesota, 308 Harvard Street, S.E., Minneapolis, MN 55455, USA

ROBERTS, J.L., The Fishberg Research Center in Neurobiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

ROQuEs, B.R., Departement de Chimie Organique, U 266 INSERM, UA 498 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, 4, avenue de l'Observatoire, F-75006 Paris, France

ROSSlER, J., Institut Alfred Fessard, Centre National de la Recherche Scientifique, F-91198 Gif-sur-Yvette Cedex, France

ROTHMAN, R.B., Laboratory of Clinical Psychopharmacology, NIDA Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224, USA

SCHAFER, M.K.H., Anatomisches Institut, Johannes-Gutenberg-Universitat, SaarstraBe 21, W-6500 Mainz, FRG

SCHILLER, P. W., Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110, avenue des Pins Ouest, Montreal, Quebec, Canada H2W 1R7

SCHOI'l'ELMEER, A.N .M., Department of Pharmacology, Free University Medical Faculty, Van der Boechorststraat 7, NL-1081 BT, Amsterdam, The Netherlands

SCOTT, R.E.M., Department of Anatomy and Cell Biology, Columbia College of Physicians and Surgeons, 630 W. 168th Street, New York, NY 10032, USA

SIMON, E.J., Departments of Psychiatry and Pharmacology, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA

SMITH, A.P., Department of Pharmacology, University of Minnesota Twin Cities, Medical School, 3-249 Millard Hall, 435 Delaware Street, S.E., Minneapolis, MN 55455, USA

SMITH, J .A.M., Department of Pharmacology, California College of Medicine, University of California, Irvine, CA 927l7, USA

SPECTOR, S., Vanderbilt University Medical School, Department of Psy­chiatry and Pharmacology, Nashville, TN 37232, USA

List of Contributors IX

TEMPEL, A., Department of Psychiatry, Hillside Hospital, Division of L.I.J.M.C., 266th Street and 16th Street Avenue, Glen Oaks, NY 11004, USA

TESCHEMACHER, H., Rudolf-Buchheim-Institut fUr Pharmakologie der Justus-Liebig-Universitat, Frankfurter StraBe 107, W-6300 GieBen, FRG

TRUJILLO, K.A., Mental Health Research Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720, USA

YOUNG, E., Mental Health Research Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720, USA

WATSON, SJ., Mental Health Research Institute, University of Michigan, 205 Washtenaw Place, Ann Arbor, MI 48109-0720, USA

WOOD, P.L., Mayo Clinic Jacksonville, 4500 San Pablo Road, Research Building 3, Jacksonville, FL 32224, USA

ZUKIN, R.S., Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461-1988, USA

HANS KOSTERLITZ

Dedication

It is a great pleasure to dedicate this volume to Professor HANS KOSTERLlTZ, of the University of Aberdeen, Scotland. Professor KOSTERLITZ is un­doubtedly one of the leaders in the opioid field, whose scientific vision has exerted a significant impact on the development of this field of research. His career represents a lifetime of successful and important research, which culminated after his official retirement, when he and his colleague, Dr. JOHN HUGHES, along with a dynamic scientific team, discovered the first endogenous opioid peptides, the enkephalins.

Dr. KOSTERLITZ received his M.D. degree in 1928 from the University of Berlin and worked in that medical school until 1933. He then decided to leave Germany and took a position in the Physiology Department at the University of Aberdeen, where Nobel laureate J.J.R. MACLEOD held the chair. His research on carbohydrate metabolism bore fruit in 1937 when he isolated galactose-I-phosphate, an important intermediate in the conversion of galactose to glucose in the liver. In 1968, Dr. KOSTERLITZ was appointed to the newly created chair of pharmacology. In 1973, he retired at the age of 70 and became professor emeritus. The same year he was named director of a new laboratory established at the University of Aberdeen, called the Unit for Research on Addictive Drugs.

Starting in the 1940s his research increasingly began to reflect his inter­est in neuroscience and particularly in the mode of action of morphine and related narcotic analgesics. In the early 1950s, he demonstrated that the isolated guinea pig ileum is an excellent bioassay system for these drugs. In spite of ridicule by scientists who felt that any work not directly concerned with the central nervous system was irrelevant, he persisted. In extensive and thorough research, he clearly demonstrated the usefulness of in vitro bioassay systems for the study of opiates. His laboratory has developed several bioassay systems in addition to the guinea pig ileum. These include the mouse vas deferens and, more recently, the hamster and rat vas deferens systems, all of which are now used throughout the world for the assay and differentiation of the various types of opioid receptors.

It was also the use of the in vitro systems that permitted HANS KOSTERLITZ and his young collaborators, most notably JOHN HUGHES, to isolate from pig brain the first endogenous peptides with opiate-like activity in 1975, which they named methionine- and leucine enkephalin. This was a

XII Dedication

major discovery which catalyzed major advances in the field of neuropeptide research, an area which has since become one of the most active in neuro­science. It is of interest that this discovery was made two years after Dr. KOSTERLITZ' official retirement.

Professor KOSTERLITZ continued his work on opioids, focusing on the mechanism of release of enkephalins and on the multiplicity of opioid receptors. His wide ranging interests have encompassed almost every level of study of endogenous opioids, from physical structure, pharmacology, regulation, to overall physiological functions. It is, therefore, fitting that this volume, which attempts to cover the multiple levels of discourse in the study of endogenous opioids, be dedicated to him.

Looking back at Professor KOSTERLITZ' career, one is struck by two remarkable characteristics: First, he has changed his areas of scientific interest more than once, and the changes have not been minor (e.g. from carbo­hydrate metabolism to endogenous opioids), and second, he made signi­ficant and lasting contributions in each of these fields.

To have altered the course of research in one area is a feat and an honor, yet to have done so repeatedly is a sign of true scientific genius. Interestingly, Professor KOSTERLITZ attributes 1 his success to the very fact that he changed his research interests during the course of his career, a process which he says suited him "temperamentally." Dr. KOSTERLITZ

asserts that "such a change creates a challenge to become familiar with new concepts and then try to compete as a newcomer." While this may crea~ "worrisome complications," he believes that the difficulties "are helpful in postponing the inevitable losses in flexibility and adaptability."

We can think of no one who better exemplifies these characteristics than Professor KOSTERLITZ. We hope that this volume will inspire similarly fresh and novel ideas among its readers.

The Editors

I From H.W. KOSTERLITZ (1979) The best laid schemes 0' mice an' men gang aft agley. Ann Rev Pharmacol Toxicol 19:1-12.

Preface

In 1957 Otto SCHAUMANN, one of the pionieers in pharmacological research on morphine and the first to prepare synthetic opiates, presented a mono­graph 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 develop­ment 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 <-QJ a. rt! 2000 a.

.... 0

<-QJ

..0 E :::J C

1000

1970 75 80 85 1990 year

Fig. 1. The number of papers published on opioids between 1970-1991 (Medline data base). Key, 0-0 endorphins, 0-0 opiate/opioid receptors, f',-f', narcotic dependence, .-. opioids (total, includes morphine, morphine derivatives, endorphins, opiate/opioid receptors, and narcotic dependence)

XIV Preface

Attempts to bring out a similar state-of-the-art volume some 10-12 years ago had to be abandoned due to the logarithmic escalation in the amount of opioid research being performed at that time. Highly stimulating and often important papers on opioid research continue to appear in large numbers, but the growth phase seems to have reached a plateau. Although our knowledge on the molecular structure of opioid receptors is still very preliminary, this seems to be an appropriate time to summarize the current status of this most stimulating research domain.

Given the immense amount of literature which has accumulated on opioids during recent years and the limited space available in this publica­tion, we were faced with the difficult task of selecting what we considered to be the most important topics of current and earlier research. We hope that our judgement was fair.

Part I deals with the multiplicity of opioid receptors (characterization, distribution, regulation etc.), the chemistry of opiates and the biochemistry and molecular biology of opioid peptides (gene expression, biosynthesis, inactivation, receptor selectivity of ligands, etc.), and the neurophysiology of opioids and their moleclular actions. Part II reviews a broad spectrum of physiological and behavioral functions and pharmacological actions of opioids. In addition, the neuroendocrinology of opioids as well as opioid tolerance and dependence are discussed in a series of chapters. The final part deals with the pathophysiology and clinical uses of opioids. Some unavoidable overlap occurs between several chapters, but the detailed subject index should help orient readers.

We would like to express our sincere thanks to the authors, who wrote their chapters without too much delay, enabling us to present up-to-date accounts. We are indepted to Prof. H. HERKEN, who initially suggested the writing of this treatise. Finally, we would like to express our gratitude to Mrs. DORIS WALKER and the other staff at Springer-Verlag as well as to our secretaries for their efforts in bringing this work to fruition.

Contents

Section A: Opioid Receptors/Multiplicity

CHAPTER 1

Opioid Receptor Multiplicity: Isolation, Purification, and Chemical Characterization of Binding Sites E.J. SIMON and T.L. GIOANNINI. With 3 Figures. . . . . . . . . . . . . . . . . . . . . 3

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 B. Opioid Receptors Exist in Multiple Types. . . . . . . . . . . . . . . . . . . . . . . 3 C. Selective Ligands for the Major Types of Opioid Receptors ....... 5 D. Characterization of Membrane-Bound Opioid Receptor Types. . . . . 6 E. Putative Endogenous Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 F. Separation and Purification of Opioid Binding Sites .............. 9

I. Solubilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 II. Physical Separation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 10

III. Affinity Cross-Linking ................................... 11 IV. Partial Purification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 V. Purification to Homogeneity .............................. 15

G. Recent Studies on Purified ~-Opioid Binding Protein . . . . . . . . . . . .. 18 I. Antibodies Generated Against Peptide Sequences. . . . . . . . . . .. 18

II. Rhodopsin Antibodies React with Purified OBP . . . . . . . . . . . .. 19 III. Attempts to Clone the cDNA of Purified OBP . . . . . . . . . . . . . .. 20

H. Concluding Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 20 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 21

CHAPTER 2

Expression Cloning of cDNA Encoding a Putative Opioid Receptor A. GOLDSTEIN. With 1 Figure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 27

A. Project History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 27 B. Expression Cloning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 28

I. Methodology ........................................... 28 II. Attempt by Stable Transfection. . . . . . . . . . . . . . . . . . . . . . . . . . .. 29

III. Transient Transfection, Panning. . . . . . . . . . . . . . . . . . . . . . . . . .. 30

XVI Contents

C. Ligand Binding by the Expressed Receptor ..................... 32 D. Sequence Analysis, Structure of the Receptor. . . . . . . . . . . . . . . . . .. 32 E. Conclusions ................................................ 35 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 35

CHAPTER 3

Characterization of Opioid-Binding Proteins and Other Molecules Related to Opioid Function A.P. SMITH, H.H. LOH, and N.M. LEE. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 37

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 37 B. cDNA Cloning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 37

I. Molecular Cloning of OBCAM . . . . . . . . . . . . . . . . . . . . . . . . . . .. 41 II. Molecular Cloning and Characterization of Gene Products

Downregulated by Chronic Opioid Treatment ofNG108-15 Cells....................................... 43

III. Use of Consensus Sequences in cDNA Cloning of Opioid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 45

C. Use of Antibodies to Characterize Opioid Receptors . . . . . . . . . . . .. 45 D. Antisense cDNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 48 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 49

CHAPTER 4

Use of Organ Systems for Opioid Bioassay J.A.M. SMITH and F.M. LESLIE. With 7 Figures 53

A. Introduction................................................ 53 I. Rationale for the Use of Isolated Organ Systems. . . . . . . . . . . .. 53

II. Tissue Preparations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 53 III. Applications of Peripheral Tissue Bioassay. . . . . . . . . . . . . . . . .. 54

B. Measurement of Pharmacological Constants. . . . . . . . . . . . . . . . . . . .. 55 I. Theoretical Considerations ... . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 55

1. Determination of Agonist Affinity ....................... 55 2. Determination of Antagonist Affinity. . . . . . . . . . . . . . . . . . . .. 57

II. Methodological Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 59 1. Choise of Tissue Preparation. . . . . . . . . . . . . . . . . . . . . . . . . . .. 59 2. Tissue Preparation and Setup. . . . . . . . . . . . . . . . . . . . . . . . . . .. 59 3. Optimization of Equilibrium Conditions .... . . . . . . . . . . . . .. 60

C. Assay Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 63 I. Guinea Pig Ileum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 63

1. Il-Receptors.......................................... 63 2. K-Receptors.......................................... 66 3. i)-Receptors.......................................... 66

Contents XVII

II. Mouse Vas Deferens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 67 1. ~-Receptors.......................................... 67 2. K-Receptors.......................................... 68 3. (i-Receptors.......................................... 69

III. Other Vasa Deferentia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 69 1. Rat Vas Deferens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 69 2. Hamster Vas Deferens ................................ 72 3. Rabbit Vas Deferens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 72

D. Conclusions ................................................ 73 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 74

CHAPTER 5

Anatomical Distribution of Opioid Receptors in Mammalians: An Overview A. MANSOUR and S.l. WATSON. With 6 Figures. . .. . . . .. . ... . . . . .. . .. 79

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 79 B. Anatomical Distributions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 81

I. ~-Receptors ............................................ 81 II. o-Receptors ............................................ 90

III. K-Receptors ............................................ 92 IV. Anatomical Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 93

C. Multiple K-Receptor Subty'pes. . .. . . .. . . .. . . .. . . . .. . ... .. . . . . .. 94 D. Nigrostriatal and Mesolimbic Dopamine Systems as Models

for Opioid Peptide and Receptor Interactions ................... 97 I. Conclusions............................................. 100

E. Future Directions ........................................... 101 References ..................................................... 102

CHAPTER 6

Opioid Receptor Regulation R.S. ZUKIN, D.E. PELLEGRINI-GIAMPIETRO, C.M. KNAPP, and A. TEMPEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 107

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 107 B. Regulation of Opioid Receptors in the Adult Brain

by Chronically Administered Opioid Agonists and Antagonists .... 110 I. Chronic Administration of Opioid Agonists In Vivo . . . . . . . . .. 110

II. Chronic Administration of Agonists to Cells Grown in Culture 111 III. Chronic Administration of Opioid Antagonists .............. 112

C. Regulation of Opioid Receptors by Other Drugs or Specific Brain Lesions ..................................... 114

D. Regulation of Opioid Receptor and Peptide Gene Expression in Embryonic and Neonatal Brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 115

XVIII Contents

I. Effects of Chronic Opioid Administration on Opioid Receptor Expression ............................ 116 1. Perinatal Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 116 2. Postnatal Treatment ................................... 117

II. Effects of Chronic Opioid Administration on Opioid Peptide Expression. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 118

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 119

CHAPTER 7

Multiple Opioid Receptors and Presynaptic Modulation of Neurotransmitter Release in the Brain A.H. MULDER and A.N.M. SCHOFFELMEER. With 4 Figures 125

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 125 B. Modulation of Noradrenaline Release. . . . . . . . . . . . . . . . . . . . . . . . .. 127 C. Modulation of Acetylcholine Release. . . . . . . . . . . . . . . . . . . . . . . . . .. 130 D. Modulation of Dopamine Release ............................. 134 E. Modulation of the Release of Other Neurotransmitters ..... . . . . .. 137 F. Conclusions ................................................ 138 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 140

CHAPTER 8

Opioid Receptor-G Protein Interactions: Acute and Chronic Effects of Opioids B.M. Cox. With 2 Figures ....................................... 145

A. Introduction................................................ 145 B. Effects of Guanine Nucleotides on Ligand Binding

to Opioid Receptors ......................................... 147 I. Opioid 11- and b-Receptors Are Funtionally Linked

to Guanine Nucleotide Binding Proteins. . . . . . . . . . . . . . . . . . .. 147 1. Guanine Nucleotides Lower Agnonist Affinity

at 11- and b-Receptors .................................. 147 2. Guanine Nucleotides Increase Agonist Dissociation Rates.. 148 3. Guanine Nucleotide Effects on Equilibrium Binding

of Opioids ........................................... 149 4. Sodium Regulates Agonist Affinity at 11- and b-Receptors. .. 156 5. Stimulation of GTPase Activity by Activation

of 11- and b-Receptors ................................. 157 II. Evidence for K-Receptor Interactions with G Proteins ........ 158

1. Effects of Guanine Nucleotides on Agonist Binding at K ,-Sites. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 159

2. Effects of Guanine Nucleotides on Binding at Kz-Sites. . . . .. 159 III. Stimulatory Effects of Opioids:

Possible Interactions of Opioid Receptors with Gs . . . . . . . . . . .. 160

Contents XIX

C. Cellular Consequences of Sustained Exposure to Opiate Drugs 162 I. Characteristics of Opioid Tolerance and Dependence. . . . . . . .. 162

II. Changes in the Number of Opioid Receptors Following Sustained Exposure to High Concentrations of Opiate Drugs .. 164 1. In Vitro Studies Employing Tissue Culture . . . . . . . . . . . . . .. 164 2. Effects of Chronic Opioid Treatment in Brain. . . . . . . . . . . .. 165 3. Effects of Chronic Treatment with K-Agonists. . . . . . . . . . . .. 167 4. Mechanisms Implicated in Changes

in Receptor Site Density. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 168 III. Chronic Opioid Treatment Uncouples Opioid Receptors

from Their Associated G Proteins. . . . . . . . . . . . . . . . . . . . . . . . .. 169 1. Receptor Desensitization; 11- and b-Receptors. . . . . . . . . . . .. 169 2. Mechanisms Implicated in Receptor Desensitization . . . . . .. 170

IV. Sustained Opioid Exposure Induces Changes in the Cellular Concentrations of Some G Proteins . . . . . . . . . .. 172 1. Neuroblastoma X Glioma (NG 108-15) Hybrid Cells. . . . . .. 172 2. Guinea Pig Ileum Myenteric Plexus ..................... 172 3. Central Nervous System ............................... 173 4. Agonist Regulation of G Protein Levels. . . . . . . . . . . . . . . . .. 173

V. Effector System Function May Be Enhanced After Sustained Opiate Drug Treatment .................... 174 1. Guinea Pig Ileum Myenteric Plexus ..................... 175 2. Neuroblastoma X Glioma (NG 108-15) Hybrid Cells ....... 175 3. Dorsal Root Ganglion-Spinal Cord Cultures. . . . . . . . . . . . .. 176 4. Locus Ceruleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 177 5. Summary ............................................ 178

VI. Summary: G Proteins and Opioid Tolerance and Dependence.. 180 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 180

CHAPTER 9

Opioid Receptor-Coupled Second Messenger Systems S.R. CHILDERS. With 3 Figures ................................... 189

A. Introduction ................................................ 189 B. G Protein Coupling to Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 190

I. General G Protein Structure and Function. . . . . . . . . . . . . . . . .. 190 II. Opioid Receptors Are Coupled to G Proteins ............... 193

C. Opioid-Inhibited Adenylyl Cyclase ............................. 194 I. Acute Effects of Opioid Agonists on Adenylyl Cyclase

in Transformed Cell Lines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 195 II. Acute Effects of Opioid Agonists on Adenylyl Cyclase

in Brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 196 III. Chronic Effects of Opioid Agonists ........................ 198 IV. Biological Roles for Opioid-Inhibited Adenylyl Cyclase ....... 201

D. Other Second Messenger Systems .............................. 203

xx Contents

I. Stimulation of Adenylyl Cyclase . . . . . . . . . . . . . . . . . . . . . . . . . .. 203 II. Cyclic GMP ............................................ 204

III. Phosphatidylinositol Turnover and Effects on Membrane Lipids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 204

IV. Opioid-Dependent Protein Phosphorylation ................. 206 E. Conclusions ................................................ 207 References ................................................... " 208

CHAPTER 10

Allosteric Coupling Among Opioid Receptors: Evidence for an Opioid Receptor Complex R.B. ROTHMAN, l.W. HOLADAY, and F. PORRECA. With 4 Figures ...... 217

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 217 B. Evidence for a ll-o-0pioid Receptor Complex ................... 217

I. Ligand-Binding Data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 217 1. Evidence that Il-Ligands Noncompetitively Inhibit

o-Receptor Binding ................................... 217 2. Evidence that o-Ligands Noncompetitively Inhibit

Il-Receptor Binding ................................... 220 II. o-Agonist - Il-Agonist Interactions ......................... 223

1. Early Studies: Analgesia Model. . . . . . . . . . . . . . . . . . . . . . . .. 223 2. More Recent Studies: Analgesia Model ................ " 224

III. Il-Antagonist - o-Antagonist Interactions ................... 228 IV. Linkage Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 229

C. Evidence for a K-Binding Site Associated with the ll-o-0pioid Receptor Complex. . . . . . . . . . . . . . . . . . . . . . . .. 230

I. In Vitro, Electrophysiological, Anatomical, and Biochemical Evidence 231 for a ll-o-0pioid Receptor Complex ....................... .

D. Conclusions ................................................ 232 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 233

Section B: Chemistry of Opioids with Alkaloid Structure

CHAPTER 11

Chemistry of Nonpeptide Opioids S. ARCHER .......... " ......................................... 241

A. Introduction ................................................ 241 B. Biosynthesis of Morphine, Codeine, and Thebaine ............. " 241 C. Morphine and Its Companions ................................ 244 D. Transformation Products of Thebaine ........................ " 247

Contents XXI

E. Morphinans ................................................ 251 F. Diene Adducts Derived from Thebaine. . . . . . . . . . . . . . . . . . . . . . . .. 255 G. 6,7-Benzomorphans .......................................... 257 H. Piperidine-Based Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 262 I . Ethylene Diamines ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 265 J . Acyclic Opioids .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 269 K. Concluding Remarks ......................................... 270 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 271

CHAPTER 12

Selective Nonpeptide Opioid Antagonists P.S. PORTOGHESE. With 8 Figures .................................. 279

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 279 B. Receptor Selectivity ......................................... 280 C. Il-Seiective Opioid Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 281 D. 8-Selective Opioid Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 282 E. K-Selective Opioid Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 288 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 291

CHAPTER 13

Presence of Endogenous Opiate Alkaloids in Mammalian Tissues S. SPECTOR and J. DONNERER. With 3 Figures ....................... 295

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 295 B. Technical Principles Used in the Isolation of Alkaloid Compounds

from Animal Tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 295 C. Identification of Endogenous Opiate Alkaloids

in Mammalian Tissue ........................................ 297 D. Biosynthesis of Mammalian Morphine .......................... 298 E. Regulation of Endogenous Morphine and Search

for a Physiological Role ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 301 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 302

Section c: Opioid Peptides

CHAPTER 14

Regulation of Opioid Peptide Gene Expression V. HOLLT. With 2 Figures ........................................ 307

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 307 B. Structure and Regulatory Elements of the Opioid Peptide Genes. .. 308

I. Proopiomelanocortin..................................... 308

XXII Contents

II. Proenkephalin .......................................... 310 III. Prodynorphin ........................................... 312

C. Gene Regulation ............................................ 313 I. Proopiomeianocortin..................................... 313

1. Adenohypophysis.................................... 313 2. Intermediate Pituitary ................................ 316 3. Hypothalamus ....................................... 318 4. Peripheral Tissues ................................... 318 5. Tumors ............................................. 319

II. Proenkephalin .......................................... 320 1. Striatum............................................ 320 2. Hypothalamus....................................... 321 3. Hippocampus and Cortex ............................. 322 4. Spinal Cord and Lower Brainstem. . . . . . . . . . . . . . . . . . . . .. 323 5. Pituitary ............................................ 323 6. Adrenal Medulla .................................... 324 7. Heart .............................................. 326 8. Gonads............................................. 327 9. Immune System ..................................... 327

10. Cell Lines ........................................... 328 Ill. Prodynorphin ........................................... 328

1. Hypothalamus ....................................... 328 2. Striatum............................................ 329 3. Hippocampus ....................................... 330 4. Spinal Cord ......................................... 331 5. Pituitary ............................................ 331 6. Peripheral Tissues ................................... 332

D. Summary................................................... 332 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 333

CHAPTER 15

Regulation of Pituitary Proopiomelanocortin Gene Expression l.L. ROBERTS, N. LEVIN, D. LORANG, l.R. LUNDBLAD, S. DERMER,

and M. BLUM. With 2 Figures .................................... 347

A. Introduction................................................ 347 I. The POMC Gene ........................................ 347

II. Intracellular Processes Regulating POMC Secretion .......... 349 B. Proopiomeianocortin mRNA Levels in Pituitary . . . . . . . . . . . . . . . .. 351

I. Whole Animal Studies ................................... 352 1. Adrenalectomy....................................... 352 2. Hypothalamic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 353 3. Intermediate Lobe POMC mRNA Levels ................ 354

II. In Vitro Systems ........................................ 355

Contents XXIII

1. Glucocorticoids....................................... 356 2. cAMP- and Calcium-Dependent Processes ............... 356

III. Summary............................................... 358 C. Proopiomelanocortin Gene Transcription . . . . . . . . . . . . . . . . . . . . . .. 358

I. Modulation of POMC hnRNA Levels . . . . . . . . . . . . . . . . . . . . .. 359 II. Whole Animal Studies ................................... 360

III. Primary and AtT20 Cell Culture. . . . . . . . . . . . . . . . . . . . . . . . . .. 361 IV. Summary............................................... 363

D. Regulatory Elements in the POMC Gene ....................... 364 I. Basal and Tissue-Specific Promoter Elements. . . . . . . . . . . . . . .. 364

II. Glucocorticoid Regulatory Elements . . . . . . . . . . . . . . . . . . . . . .. 367 III. Promoter Elements and Second Messenger Pathways. . . . . . . .. 368 IV. Summary ............................................... 369

E. Conclusions ................................................ 370 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 341

CHAPTER 16

Molecular Mechanisms in Proenkephalin Gene Regulation N. KLEY and J.P. LOEFFLER ....................................... 379

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 379 B. Cellular Signaling Pathways Mediating PENK Gene Induction ..... 380

I. Membrane Associated Events and Second Messengers. . . . . . .. 380 1. Regulation of PENK Gene Expression by Electrical Activity

and Ca2+ Metabolism in Excitable Cells. . . . . . . . . . . . . . . . .. 380 2. Cyclic AMP as a Regulator of PENK Gene Expression. . . .. 381 3. Phosphoinositide Hydrolysis and PENK Gene Regulation .. 381

II. Regulation of PENK Gene Expression by Third Messengers ... 382 C. Mechanisms of PENK Gene Transcriptional Regulation .......... 383

I. Transcriptional Regulation of the Endogenous PENK Gene . .. 384 II. Gene Transfer Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 385

III. DNA-Responsive Elements ............................... 387 D. Summary ................................................... 389 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 390

CHAPTER 17

Proopiomelanocortin Biosynthesis, Processing and Secretion: Functional Implications E. YOUNG, D. BRONSTEIN, and H. AKIL. With 1 Figure ............... 393

A. Introduction................................................ 393 B. Tissue-Specific Processing .................................... 394

I. Anterior Lobe .......................................... 394 II. Intermediate Lobe ....................................... 396

XXIV Contents

III. Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 397 C. Proopiomelanocortin Processing and Modifying Enzymes . . . . . . . .. 400 D. Possible Functional Significance of Posttranslational Modifications

to POMC-Derived Peptides ................................... 401 I. Anterior Lobe .......................................... 403

II. Intermediate Lobe. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 404 III. Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 405

1. Central Analgesia, Tolerance and Dependence. . . . . . . . . . .. 405 2. Reinforcement ....................................... 408 3. Autonomic Functions ................................. 409

IV. Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 410 E. Conclusion ................................................. 412 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 413

CHAPTER 18

Biosynthesis of Enkephalins and Proenkephalin-Derived Peptides J. ROSSlER. With 5 Figures ....................................... 423

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 423 B. History .................................................... 424 C. Enkephalin Biosynthesis in the Adrenal Medulla. . . . . . . . . . . . . . . .. 425 D. Molecular Biology ........................................... 431 E. Enkephalin Biosynthesis in the CNS ........................... 433 F. Synenkephalin .............................................. 436 G. Molecular Evolution of Proenkephalin ......................... 437 H. Extraneuronal Proenkephalin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 438

I. Reproductive Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 438 II. Glial Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 438

III. Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 439 I. Processing of Proenkephalin .................................. 439 J. Regulation................................................. 440 K. Conclusion ................................................. 441 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 441

CHAPTER 19

Prodynorphin Biosynthesis and Posttranslational Processing R. DAY, K.A. TRUJILLO, and H. AKIL. With 2 Figures ............... 449

A. History of Dynorphin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 449 B. Posttranslational Processing Signals ............................ 450 C. Prodynorphin Biosynthesis and Processing in Peripheral Tissues ... 451 D. Processing Pathway of Prodynorphin ........................... 453

Contents XXV

E. Functional Significance of Prodynorphin Peptide Processing . . . . . .. 458 I. Striatonigral System ..................................... 461

II. Other Systems .......................................... 463 F. Conclusions ................................................ 463 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 463

CHAPTER 20

Anatomy and Function of the Endogenous Opioid Systems H. KHACHATURIAN, M.K.H. SCHAFER, and M.E. LEWIS. With 1 Figure ................................................ " 471

A. Introduction ................................................ 471 B. Immunocytochemical Anatomy of Opioid Systems ............. " 472

I. Proopiomelanocortin..................................... 472 II. Pro en kephalin .......................................... 473

III. Prodynorphin ......................................... " 474 C. In Situ Hybridization Histochemical Studies ................... " 475

I. Proopiomelanocortin mRNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 476 II. Proenkephalin and Prodynorphin mRNA ................. " 477

III. Expression of Opioids in Nonneuronal Cells ................. 481 D. Opioid Receptors and Functional Systems ...................... 482

I. Problems in the Functional Analysis of Endogenous Opioid Systems. . . . . . . . . . . . . . . . . . . . . . . . . . .. 482

II. Opioid Peptide-Receptor Relationships ..................... 483 E. Functional Roles of Opioid Systems .......................... " 484

I. Endogenous Pain Control Systems. . . . . . . . . . . . . . . . . . . . . . . .. 484 II. Extrapyramidal Motor Systems . . . . . . . . . . . . . . . . . . . . . . . . . . .. 486

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 488

CHAPTER 21

Atypical Opioid Peptides H. TESCHEMACHER .............................................. 499

A. Introduction .............................................. " 499 I. Atypical Representatives of Natural Opioid Peptides

(Atypical Natural Opioid Peptides) ........................ 499 II. Peptides with Indirect Opioid or Opioid Antagonist Activity. " 499

B. Atypical Opioid Peptides ..................................... 501 I. Structure and Activity .................................... 501

1. a-Casein Exorphins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 512 2. ~-Casomorphins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 512 3. ~-Casorphin, a- and ~-Lactorphins ...................... 513

XXVI Contents

4. Hemorphins and Cytochrophins. . . . . . . . . . . . . . . . . . . . . . . .. 513 5. Dermorphins and Deltorphins .......................... 513

II. Origin and Destination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 515 1. Milk Protein-Derived Opioid Peptides ................... 515 2. Hemoglobin- or Cytochrome b-Derived Opioid Peptides ... 516 3. Amphibian Skin Protein-Derived Opioid Peptides ......... 517

C. Opioid Antagonists Sharing Characteristics with Atypical Opioid Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 517

I. Structure and Activity ................................... , 518 1. Casoxins............................................. 518 2. Lactoferroxins........................................ 518

II. Origin and Destination .................................. , 518 D. Atypical Opioid Peptide Analogues with Agonist

or Antagonist Activity ....................................... 518 I. Agonists ............................................... 521

1. Il-Selective Opioid Receptor Ligands .................... 521 2. o-Selective Opioid Receptor Ligands .................... 521

II. Antagonists............................................. 521 E. Concluding Remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 521 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 522

CHAPTER 22

Opioid Peptide Processing Enzymes L.D. FRICKER ......... , .... , .................................... 529

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 529 B. Enzymes in the Endoplasmic Reticulum and Golgi Apparatus ..... 531

I. Signal Peptidase ......................................... 531 II. Glycosylation, Sulfation, and Phosphorylation. . . . . . . . . . . . . .. 531

C. Enzymes in the Secretory Granules ............................ 533 I. Endopeptidases Selective for Paired Basic Residues . . . . . . . . .. 534

II. Opioid Peptide Processing Endopeptidases Selective for Single Basic Residues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 536

III. Carboxypeptidase E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 537 IV. Aminopeptidase B-Like Enzyme .......................... 539 V. Amidation.............................................. 539

VI. Acetylation............................................. 540 D. Extracellular Opioid Peptide Processing Enzymes ................ 541 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 541

Contents

CHAPTER 23

Peptidase Inactivation of Enkephalins: Design of Inhibitors and Biochemical, Pharmacological and Clinical Applications B.P. ROQUES, A. BEAUMONT, V. DAUGE, and M.-C. FOURNIE-ZALUSKI.

XXVII

With 2 Figures ................................................. 547

A. Introduction................................................ 547 B. Enkephalin Degrading Enzymes ............................... 548

I. Metabolism of Opioid Peptides . . . . . . . . . . . . . . . . . . . . . . . . . .. 548 II. Substrate Specificity of NEP and APN . . . . . . . . . . . . . . . . . . . .. 550

III. Assays of NEP and APN Activities. . . . . . . . . . . . . . . . . . . . . . .. 551 C. Structure and Molecular Biology of NEP ....................... 551

I. Structure of NEP ....................................... 551 II. Human NEP (CALLA) Gene ............................ 553

D. Localization of Neutral Endopeptidase 24.11 .................... 553 I. Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 553

II. Localization of NEP in Peripheral Tissues. . . . . . . . . . . . . . . . .. 555 III. In Vitro and In Vivo Studies of Enkephalin Degradation

by NEP and APN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 555 E. Inhibitor Design and Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 556

I. Design of Selective and Mixed Inhibitors of Neutral Endopeptidase 24.11 and Aminopeptidase N . . . . .. 556

II. Thiol Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 557 III. Carboxyl Inhibitors ..................................... 559 IV. Hydroxamic Acids and Derivatives ........................ 561 V. Phosphorus-Containing Inhibitors ......................... 563

VI. Aminopeptidase-N and Dipeptidyl Peptidase Inhibitors . . . . .. 563 VII. Development of Mixed Inhibitors

of Enkephalin-Degrading Enzymes ........................ 563 F. Pharmacological Studies of Enkephalin-Degrading-Enzyme

Inhibitors .................................................. 564 I. Inhibitor-Induced Analgesia .............................. 565

II. Inhibitor-Induced Spinal Antinociception .................. 566 III. Peptidase Inhibitors in Chronic Pain. . . . . . . . . . . . . . . . . . . . . .. 567 IV. Tolerance, Dependence, and Side Effects of Selective

and Mixed Inhibitors of NEP and APN . . . . . . . . . . . . . . . . . . .. 567 V. Gastrointestinal Effects .................................. 568

VI. Role of Neutral Endopeptidase-24.11 in Airways. . . . . . . . . . .. 569 VII. Behavioral Effects of Inhibitors ........................... 569

XXVIII Contents

G. Inhibition of NEP Inactivation of Atrial Natriuretic Peptide: Pharmacological and Clinical Implications ...................... 570

H. Clinical Applications of Selective and Mixed Zn Metallopeptidase Inhibitors .................................................. 571

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 572

CHAPTER 24

Coexistence of Opioid Peptides with Other Neurotransmitters R. ELDE and T. HOKFELT. With 6 Figures .......................... 585

A. Principles .................................................. 585 I. Introduction........................................... 585

II. Subcellular Features. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 588 1. Classical Neurotransmitters and Small Synaptic Vesicles .. 589 2. Neuropeptides and Large Granular Vesicles ............. 590

III. Methods for Establishing Coexistence ..................... 590 B. Coexistence Within Areas of the Nervous System . . . . . . . . . . . . . . .. 592

I. Retina................................................ 593 II. Telencephalon......................................... 601

III. Diencephalon ......................................... 602 IV. Mesencephalon........................................ 603 V. Pons and Medulla. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 603

VI. Cerebellum ........................................... 606 VII. Spinal Cord ........................................... 606

VIII. Peripheral Nervous System. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 607 1. Primary Afferent Neurons. . . . . . . . . . . . . . . . . . . . . . . . . . .. 607 2. Autonomic Ganglion Cells and Their Fibers. . . . . . . . . . . .. 608 3. Adrenal Medulla .................................... 609 4. Enteric Nervous System .............................. 609

C. Implications ................................................ 6U I. Patterns of Expression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 611

II. Pharmacology and Physiology ........................... 612 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 612

CHAPTER 25

Interrelationships of Opioid, Dopaminergic, Cholinergic and GABAergic Pathways in the Central Nervous System P.L. WOOD. With 2 Figures ...................................... 625

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 625 B. Cholinergic Systems ......................................... 625

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 625 II. Septohippocampal Cholinergic Pathway .................... 625

Contents XXIX

III. Nucleus Basalis-Cortical Cholinergic Pathway .. . . . . . . . . . . . .. 626 C. Dopaminergic Pathways. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 628

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 628 II. Nigrostriatal Pathway .................................... 629

III. Mesolimbic Pathways .................................... 632 IV. Mesocortical Pathways ................................... 633

D. GABAergic Pathways ........................................ 634 E. Striatal Opioid Peptide Gene Expression ....................... 635

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 635 II. Met- Enkephalin ........................................ 635

III. Dynorphin ............................................. 637 F. Conclusions ................................................ 637 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 638

CHAPTER 26

Selectivity of Ligands for Opioid Receptors A.D. CORBETI, S.l. PATERSON, and H.W. KOSTERLITZ ................ 645

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 645 B. Methods Used to Determine the Selectivity of Opioid Compounds .. 645

I. Radioreceptor Binding Assays ............................ 646 II. Bioassays ............................................... 647

C. Selectivity of Endogenous Opioid Peptides . . . . . . . . . . . . . . . . . . . . .. 648 I. Proenkephalin-Derived Peptides ........................... 650

1. Activity in Binding Assays ... . . . . . . . . . . . . . . . . . . . . . . . . .. 650 2. Activity in Bioassays ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 650

II. Prodynorphin-Derived Peptides ........................... 651 1. Activity in Binding Assays ............................. 651 2. Activity in Bioassays .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 653

III. Proopiomelanocortin-Derived Peptides ..................... 653 1. Activity in Binding Assays ... . . . . . . . . . . . . . . . . . . . . . . . . .. 653 2. Activity in Bioassays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 655

IV. Dermorphin and Deltorphins ............................. 655 1. Activity in Binding Assays .. . . . . . . . . . . . . . . . . . . . . . . . . . .. 655 2. Activity in Bioassays ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 657

D. Selectivity of Nonendogenous Opioid Compounds ............... 657 I. Compounds with a Preference for the Il-Binding Site ......... 660

1. Activity in Binding Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 660 2. Agonist Activity in Bioassays . . . . . . . . . . . . . . . . . . . . . . . . . .. 662 3. Antagonist Activity in Bioassays . . . . . . . . . . . . . . . . . . . . . . .. 662

II. Compounds with a Preference for the o-Binding Site ......... 663 1. Activity in Binding Assays .... . . . . . . . . . . . . . . . . . . . . . . . .. 663 2. Agonist Activity in Bioassays . . . . . . . . . . . . . . . . . . . . . . . . . .. 668 3. Antagonist Activity in Bioassays . . . . . . . . . . . . . . . . . . . . . . .. 668

xxx Contents

Ill. Compounds with a Preference for the K-Binding Site ......... 669 1. Activity in Binding Assays .. . . . . . . . . . . . . . . . . . . . . . . . . . .. 669 2. Agonist Activity in Bioassays . . . . . . . . . . . . . . . . . . . . . . . . . .. 669 3. Antagonist Activity in Bioassays . . . . . . . . . . . . . . . . . . . . . . .. 669

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 673

CHAPTER 27

Development of Receptor-Selective Opioid Peptide Analogs as Pharmacologic Tools and as Potential Drugs P.W. SCHILLER. With 2 Figures ................................... 681

A. Introduction................................................ 681 B. Determination of Receptor Selectivity. . . . . . . . . . . . . . . . . . . . . . . . .. 683 C. Development of 11-, 0-, and K-Receptor-Selective Opioid Peptide

Analogs with Agonist Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 684 I. I1-Selective Agonists ..................................... 684

1. Linear Opioid Peptide Analogs . . . . . . . . . . . . . . . . . . . . . . . .. 684 2. Opioid Peptide Dimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 688 3. Cyclic Opioid Peptide Analogs .......................... 689

II. o-Selective Agonists ..................................... 692 1. Linear Opioid Peptide Analogs . . . . . . . . . . . . . . . . . . . . . . . .. 692 2. Opioid Peptide Dimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 696 3. Cyclic Opioid Peptide Analogs. . . . . . . . . . . . . . . . . . . . . . . . .. 696

III. K-Selective Agonists ..................................... 697 D. Selective Opioid Peptide Analogs with Antagonist Properties. . . . .. 697 E. Irreversible Opioid Receptor Peptide Ligands . . . . . . . . . . . . . . . . . .. 699

1. Chemical Affinity Labels .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 699 II. Photoaffinity Labels ..................................... 699

F. Selective Opioid Peptide Analogs as Drug Candidates ............ 701 G. Conclusions ................................................ 703 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 704

CHAPTER 28

Ontogeny of Mammalian Opioid Systems J.E. PINTAR and R.E.M. SCOTT ................................... 711

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 711 B. Embryological Considerations ................................. 711 C. Opioid Gene Activation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 712

I. Proopiomelanocortin..................................... 712 1. Brain ............................................... 712 2. Pituitary............................................. 713 3. Testis ............................................... 714 4. Placenta ............................................. 714

Contents XXXI

II. Enkephalin ............................................. 714 1. Brain (Striatal) .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 715 2. Glia ................................................. 715 3. Fetal Mesoderm ...................................... 716

III. Dynorphin ............................................. 716 D. Ontogeny of Opioid Precursor Processing. . . . . . . . . . . . . . . . . . . . . .. 717

I. Proopiomelanocortin..................................... 717 1. Immunocytochemical Analyses ......................... 717 2. Biochemical Analyses ................................. 718

II. Dynorphin ............................................. 718 E. Ontogeny of Regulated Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 719

I. Secretory Granules, Regulators of POMC Secretion and the Portal System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 719

II. Functional Receptors for Secretagogues .................... 720 F. Function ................................................... 721

I. Ontogeny of Opioid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . .. 721 II. Putative Role(s) of Opioid Peptides

in Developmental Processes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 723 G. Prospectus.................................................. 723 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 724

Section D: Neurophysiology

CHAPTER 29

Opioids and Sensory Processing in the Central Nervous System A.W. DUGGAN and S.M. FLEETWOOD-WALKER. With 4 Figures 731

A. Introduction ................................................ 731 B. Opioids and the Spinal Cord .................................. 731

I. Spinal Processing of Nociceptive Information ................ 731 II. Systemic Administration of Opiates and the Responses

of Spinal Neurones ...................................... 732 1. Neuronal Types ...................................... 733 2. Responses to Peripheral Stimuli. . . . . . . . . . . . . . . . . . . . . . . .. 733

III. Localized Administration of Opioids . . . . . . . . . . . . . . . . . . . . . .. 736 1. I!-Receptor-Preferring Ligands ........................ " 737 2. o-Receptor-Preferring Ligands ........................ " 740 3. K-Receptor-Preferring Ligands .......................... 741

IV. Functional Consequences of Opioid Receptor Activation to Spinal Sensory Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 743 1. Opioid Receptors and the Central Terminals of Nociceptors 743 2. Receptors on the Somata and Processes of Spinal Neurones 745 3. Receptors and Supraspinal Fibres ....................... 747

XXXII Contents

V. Opiates and Descending Inhibition ......................... 748 VI. Physiological Roles of Opioid Peptides in Sensory Processing .. 749

1. Spinal Release of Opioid Peptides . . . . . . . . . . . . . . . . . . . . . .. 750 2. Tonic Opioidergic Inhibition ........................... 750 3. Phasic Opioidergic Inhibition ........................... 752

C. Thalamus and Cerebral Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 753 I. Thalamus .............................................. 753

1. Ventrobasal Nuclei .................................... 753 2. Medial and Dorsal Thalamic Nuclei ..................... 755

II. Cerebral Cortex ......................................... 757 D. Deficits in Knowledge and Prospects for Future Research ......... 758 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 760

CHAPTER 30

Opioid Actions on Membrane Ion Channels R.A. NORTH. With 4 Figures ..................................... 773

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 773 B. Calcium Channels ........................................... 774

I. Types of Calcium Channels .............................. 774 II. Il-Receptors ........................................... 775

III. (i-Receptors ........................................... 775 IV. K-Receptors ........................................... 777 V. Unclassified Receptors .................................. 777

VI. Experiments on Action Potential Duration ................ 777 VII. Type of Calcium Current Inhibited ....................... 778

VIII. Mechanism of Opioid Action . . . . . . . . . . . . . . . . . . . . . . . . . . .. 778 1. Role of G Proteins .................................. 778 2. Time Course of Agonist Action ....................... 779 3. Single Channel Studies ............................... 780 4. Voltage Dependence of Agonist Action? ............... 780

IX. Other Receptors That Reduce Calcium Currents .. . . . . . . . .. 780 X. Calcium Current Inhibition and Presynaptic Inhibition ...... 781

C. Potassium Channels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 781 I. Types of Potassium Channels. . . . . . . . . . . . . . . . . . . . . . . . . . .. 781

II. Il-Receptors ........................................... 782 III. (i-Receptors ........................................... 782 IV. Other Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 784 V. Experiments on Action Potential Duration ................ 784

VI. Hyperpolarization and Inhibition of Firing ................. 784 VII. Type of Potassium Current Increased ..................... 784

VIII. Mechanism of Opioid Action ............................ 787

Contents XXXIII

1. Role of G Proteins .................................. 787 2. Time Course of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 788 3. Single Channel Studies ............................... 788

IX. Other Receptors That Increase Potassium Conductance . . . .. 790 X. Potassium Conductance Increase and Presynaptic Inhibition 790

D. Other Ion Channels .......................................... 791 E. Changes in Tolerance and Dependence. . . . . . . . . . . . . . . . . . . . . . . .. 791 F. Concluding Remarks ......................................... 792 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 793

Subject Index .................................................. 799

Contents of Companion Volume 104, Part II

Section E: Pharmacology and Behavior

CHAPTER 31 Brainstem Mechanisms of Pain Modulation: Anatomy and Physiology H.L. FIELDS

CHAPTER 32 Supraspinal Opioid Receptors in Antinociception. F. PORRECA and T .F. BURKS

CHAPTER 33 The Spinal Actions of Opioids. T. L. Y AKSH

CHAPTER 34 Peripheral Mechanisms of Opioid Analgesia. C. STEIN

CHAPTER 35 Acupuncture and Stimulation-Produced Analgesia. lI-SHENG HAN

CHAPTER 36 Multiple Opioid Systems and Chronic Pain. M.l. MILLAN

CHAPTER 37 Gastrointestinal Effects of Opioids. W. KROMER

CHAPTER 38 Role of Endogenous Opioids in Central Cardiovascular Regulation and Dysregulation. A.1. FADEN

CHAPTER 39 Physiological Functions of Opioids: Temperature Regulation. M.W. ADLER and E.B. GELLER

CHAPTER 40 Opioid Mechanisms in the Control of Food Consumption and Taste Preferences. S.l. COOPER and T.e. KIRKHAM

CHAPTER 41 Opioids in Respiration and Vomiting. 1. FLOREZ and M.A. HURLE

CHAPTER 42 Opioid Systems and Stress. R. PRZEWLOCKI

XXXVI Contents of Companion Volume 104, Part II

CHAPTER 43 Role of Endogenous Opioids and Opioid Receptors in the Central Nervous System Injury. A.I. FADEN

CHAPTER 44 Opioids: Epilepsy and Neuroprotection. F.C. TORTELLA

CHAPTER 45 Opioids in Immunologic Processes. H.U. BRYANT and J.W. HOLADAY

CHAPTER 46 Effects of Opioids on the Spontaneous Behavior of Animals. A. Cow AN

CHAPTER 47 Involvement of Opioid Peptides in Learning and Memory. J. L. MCGAUGH, I.B. INTROINI-COLLISON, and C. CASTELLANO

CHAPTER 48 Correlations Between the Pharmacodynamic Characteristics of Opioid Agonists and Their Behavioral Effects. A.J. BERTALMIO, c.P. FRANCE, and J.H. WOODS

Section F: Neuroendocrinology

CHAPTER 49 Opioid Peptides in the Regulation of Anterior Pituitary Hormones. S.G. CELLA, V. LOCATELLI, and E.E. MULLER

CHAPTER 50 Opioids and the Neuroendocrine Control of Reproduction. O.F.X. ALMEIDA

CHAPTER 51 Opioids in the Neurohypophysial System. R.J. BICKNELL

CHAPTER 52 Opioid Peptide Expression in Peripheral Tissues and Its Functional Implications. D.L. KILPATRICK

Section G: Reinforcement - Tolerance/Dependence

CHAPTER 53 Opioid Tolerance and Physical Dependence and Their Relationship. E.L. WAY

Contents of Companion Volume 104, Part II

CHAPTER 54 Opioid Tolerance/Dependence in Isolated Organs. R. SCHULZ

CHAPTER 55 Opioid Abuse Liability Assessment in Rhesus Monkeys. J.H. WOODS, c.P. FRANCE, G. WINGER, A.J. BERTALMIO, K. SCHWARZ-STEVENS

CHAPTER 56 Motivational Effects of Opioids. T.S. SHIPPEN BERG

Section H: Clinical Aspects

CHAPTER 57 CSF Opioids in Pathophysiology. F. NYBERG

CHAPTER 58 Circulating Opioids in Man. L. McLoUGHLIN, S. MEDBACK, and A.B. GROSSMAN

CHAPTER 59 Opioid Analgesics in Clinical Pain Management. K.M. FOLEY

CHAPTER 60 Opioids in Operative Anesthesia. P.L. BAILEY

CHAPTER 61 p-Endorphin in Human Reproduction. F. PETRAGLIA, G. COMITINI, and A.R. GENAZZANI

CHAPTER 62 Opioids in the Etiology and Treatment of Psychiatric Discorders. D. NABER

CHAPTER 63 Opioid Addiction. c.P. O'BRIEN

Subject Index

XXXVII