Enkephalins and Endorphins Stress and the Immune System Enkephalins and Endorphins Stress and the Immune System Edited by Nicholas P. Plotnikoff Oral Roberts University Tulsa, Oklahoma Robert E. Faith University of Houston Houston, Texas Anthony J. Murgo West Virginia University Morgantown, West Virginia and Robert A. Good University of South Florida St. Petersburg, Florida SPRINGER SCIENCE+BUSINESS MEDIA, LLC Library of Congress Cataloging in Publication Data Enkephalins and endorphins. Bibliography: p. Includes index. 1. Enkephalins-Physiological effect. 2. Endorphins-Physiological effect. 3. Immune re sponse-Regulation. 4. Stress (Physiology) 5. Stress (Psychology) 6. Psychoneuroimmuno endocrinology. I. Plotnikoff, Nicholas P. QP552.E55E55 1986 616.07'9 85-23234 ISBN 978-1-4899-0559-8 ISBN 978-1-4899-0557-4 (eBook) DOI 10.1007/978-1-4899-0557-4 © 1986 Springer Science+Business Media New York Originally published by Plenum Press, New York in 1986 Softcover reprint of the hardcover 1st edition 1986 All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher FOREWORD Is this a time for a sleeping giant to rise? We have known since study of the lymphocyte and plasma cells really began in earnest in the early 1940's that the pituitary adrenal axis under intimate control of the hypothalamus could influence immunological functions profoundly. We have also known for at least 20 years in my recollection that female sex hor mones can maximize certain immunity functions while male sex hormones tend to suppress many immunological reactions. The thyroid hormones accelerate antibody production while at the same time sp~eding up de gradation of antibodies and immunoglobulins and thyroidectomy decreases the rate of antibody production. Further, much evidence has accumulated indicating that the brain, yes even the mind, can influence in significant ways susceptibility to infections, cancers and to development of a variety of autoimmune diseases. More than 20 years ago, my colleagues and I convinced ourselves, if no one else, that hypnosis can exert major in fluences on the effector limb of the classical atopic allergic reactions. We showed with Aaron Papermaster that the Prausnitz-Kustner reaction may be greatly inhibited, indeed largely controlled, by post-hypnotic suggestion. And it was not even necessary for us to publish our discovery because scientists in John Humphrey's laboratory at Mill Hill Research Center in London had beaten us to the punch. They described hypnotic control of both the PK reaction and delayed allergic reactions to tuberculin by hypnosis. Although he doesn't necessarily attribute the controls to neurological modulation, I have been convinced that the extraordinary rhythms Franz Halberg in Minnesota has elucidated for immunological functions that range from NK cell activity to the amount of antibody produced and even the tempo of allograft rejection reflect neuroendocrin ological interactions with the immunological systems. Halberg's Chronoimmunologic analyses have been underway for at least 20 years and would have begun earlier and progressed even more rapidly than they have had we immunologists been more responsive to his prodding and that of other chronobiologists associated with him. Why then does the present moment strike me as so propitious a moment for a comprehensive new work considering the interaction of the major body networks? For me, a new and truly golden age of psychoneuroimmunoendocrinology began when Wybran of Brussels first observed in 1979 that met-enkephalin v can talk to lymphocytes directly and its conversation with lymphocytes can be interrupted by naloxone. These rather crude beginnings have now been greatly refined and we know for sure that lymphocytes have receptors for met-enkephalin and have either surface or cytosolic receptors for a number of other hormones and neurohumoral mediators. We see in this volume and in numerous contemporary articles reaching our scientific journals that met-enkephalin, leu enkephalin and endorphins can repro ducibly influence cell surface expression and functions of lymphocytes in vivo, antibody production, delayed allergic reactions and development and differentiation of lymphoid cells. We are even witnessing these days the first descriptions of responses of immunoparameters in healthy humans and patients with various kinds of immunodeficiencies including patients with AIDS and cancer. All this is happening right now and this science and this form of immunopharmacology will be rapidly developed in the years ahead. But this is only one of many many exciting fields in psychoneuro immunoendocrinology where incredible discoveries are turning up. As a Visiting Professor at the University of Texas Medical Branch in Galveston last winter, I was introduced to a constellation of related studies by Blalock and his group of young colleagues. These studies established to my satisfaction that lymphocytes, like pituitary cells, can produce a molecule very like ACTH both immunologically and functionally and that like cells of the anterior pituitary, the lymphocytes have cyto solic receptors for cortisol. Through these, cortisol can suppress production of the ACTH-like molecule by these cells. As a classical cellular immunologist such a turn of events could never have entered my mind yet here it was, big as life, and it had been demonstrated by what seemed to me to be commanding and critical scientific methodology. But these surprises are at least paralleled as surprises presented by Hall and Goldstein's (Washington) discovery that thymosin a1 now a fully defined molecule (thymic hormone?) exerts functional and electrical influences on certain hypothalamic nuclear cells that can, in turn, exert influences on lymphoid cell function through the thymus. If these de scriptions sound fanciful it is because I believe they are. Yet they and much, much more are presented in detail in this volume of collected multi-authored papers that reflect a burgeoning scientific field. Even Robert Ader and Nicholas Cohen's exciting discovery that the immune response can be regulated by taste via prior conditioning in the conditioned -aversion response after simultaneous exposure to a cytotoxic immuno suppressive chemical may before long be explained in precise immunopharm cological terms. I now would bet it will. This field is developing more rapidly than I thought could ever be the case and I am thankful to the immunopharmacologists like Plotnikoff, Wybran, Hadden, Szentivanyi and others who have urged me to pay close attention. Robert A. Good, M.D., Ph.D. vi CONTENTS ENKEPHALINS-ENDORPHINS: STRESS AND THE IMMUNE SYSTEM Introduction: The Ying-Yang Hypothesis of Immunomodulation 1 N.P. Plotnikoff, A.J. Murgo, R.E. Faith, and R.A. Good STRESS AND THE IMMUNE SYSTEM Candidate Opioid Peptides for Interaction with the Immune System • • • • • • • • • • • • • 3 C.J. Evans, E. Erdelyi, and J.D. Barchas Control Mechanisms in the Enzyme Hydrolysis of Adrenal Released Enkephalins • • • • • • • • • • • • • • 17 L.G. Roda, G. Roscetti, R. Possenti, F. Venturelli, and F. Vita Studies of the Endogenous Opioid System in the Human Stress Response • • • • • • • • • • • • 35 M.R. Cohen, D. Pickar, M. Dubois, and R.M. Cohen Exercise Stress and Endogenous Opiates 47 P.A. Farrell and A.B. Gustafson Effects of Coping and Noncoping with Stressful Events on the Immune System • • • • • • • • • • • • • • • • 59 W. H. Vogel Depression, Hormones and Immunity 69 Z. Kronfol and J. Schlechte Endogenous Opiod Systems, Stress, and Cancer • • • • • • • • • • • 81 I.S. Zagon and P.J. McLaughlin Effects of Stress and Morphine on Natural Killer Cell Activity and on the Mammary Tumor Development 101 J.W. Lewis, Y. Shavit, F.C. Martin, G.W. Terman, R.P. Gale, and J.C. Liebeskind Endocrine and Immunological Responses to Acute Stress 109 F. Berkenbosch, C.J. Heijnen, G. Croiset, C. Revers, R.E. Ballieux, R. Binnekade, and F.J.H. Tilders REGULATORY CIRCUITS OF THE IMMUNE, ENDOCRINE AND NERVOUS SYSTEM A Complete Regulatory Loop Between the Immune and Neuro endocrine Systems Operates Through Common Signal Molecules (Hormones) and Receptors • • • • • • • • 119 E.M. Smith and J.E. Blalock vii Endorphins: A Link Between Personality, Stress, Emotions, Immunity, and Disease? • 129 G.S. Solomon, N. Kay, and J.E. Morley Involvement of Non-Opiate Peptides in Psychoneuroimmunological Modulations • • • • • • • • • • • • • • • • • • • • • • 145 S. V. Klusa, R. Muceniece, Svirskis, E. Kukaine, M. Ratkevica, G. Rosenthal, and G. Afanasyeva Regulation of Human Cellular Immune Responses by Glucocorticosteriods • • • • • • • • • • • 159 G.C. Tsokos and J.E. Balow Estrogen-Mediated Immunomodulation 173 O.J. Pung, A.N. Tucker, and M.I. Luster Effects on the Immune System of Lesioning and Stimulation of the Nervous System: Neuroimmunomodulation 189 B.D. Jankovic and N.H. Spector EFFECTS OF ENKEPHALINS/ENDORPHINS AND RELATED SUBSTANCES ON SPECIFIC IMMUNE FUNCTIONS Enkephalins: Mediators of Stress-Induced Immunomodulation. 221 A.J. Murgo, R.E. Faith, and N.P. Plotnikoff Relationship Between Lymphokine and Opiatergic Modulation of Lymphocyte Proliferation • • •••••••• 241 W.L. Farrar Enkephalins as Molecules of Lymphocyte Activation and Modifiers of the Biological Response • • • • • • 253 J. Wybran The Influence of Endogenous Opioid Peptides on Venous Granulocytes • • • • • • • • • 263 E.G. Fischer and N.E. Falke Immunosuppressive Effects of the Opiopeptins 273 H.W. McCain, I.B. Lamster, and J. Bilotta T-Cell E-Receptor Modulation By Opiates, Opiods and Other Behaviorally Active Substances • • • • • 289 R. Donahoe, J. Madden, F. Hollingsworth, D. Shafer and A. Falek Significant Role of Receptor Coupling in the Neuropeptide Induced Alterations of Macrophage Cytotoxicity 303 G. Foris, G.A. Medgyesi, and J.I. Szekely Hormonal Modulation of the Human Autologous Mixed Lymphocyte Reaction ••• 321 G.J.M. Maestroni Implications Involving Autoimmune Mechanisms to the PCP Receptor in Schizophrenia, • • • • • • • • • • • 337 H.D. Whitten, K.Y. Tsang, P. Arnaud, N.K. Khansari, and H.H. Fudenberg Effects of Morphine Opiates on Immune Function • • • • • • • • • • 347 H. Koyuncuoglu and Mehmet Gungor viii Opioid Peptide Effects on Leukocyte Migration •• 367 S.L. Brown, S. Tokuda, L.C. Saland, and D. Van Epps Neuropeptides are Chemoattractants for Human Monocytes and Tumor Cells: A Basis for Mind-Body Communication. 387 M.R. Ruff and C.B. Pert EARLY CLINICAL TRIALS OF METHIONINE ENKEPHALIN(IN VIVO) Methionine Enkephalin: Irnrnunomodulator in Normal Volunteers (In Vivo) • • • • • • • • • • • • • • • • • 399 N.P,-plotnikoff, G.C. Miller, S. Solomon, R.E. Faith L. Edwards, and A. J. Murgo Methionine Enkephalin: Clinical Pharmacology • • • • • • 407 N.P. Plotnikoff, S. Solomon, J.L. Valentine, M. Fesen, R.E. Faith, L. Edwards, R. Richter, A.J. Murgo, and G.C. Miller Methionine Enkephalin: T-Cell Enhancement in Normal Volunteers (In Vivo) • • • • • • • • • • • • • • • • • 417 N.P,-plotnikoff, G.C. Miller, S. Solomon, R.E. Faith, L. Edwards, and A.J. Murgo Methionine Enkephalin: Enhancement of T-Cells in Patients with Kaposis' Sarcoma, AIDS, and Lung Cancer (In Vivo). 425 N.P. Plotnikoff, J. Wybran, N.F. Nimeh, and G.C. Miller EPILOGUE ••• , •• 431 R.E. Faith, A.J. Murgo, and N.P. Plotnikoff CO NT RIB UTORS. • • • • • • • • • • . • • • • • , • • • • • , • • • 4 35 INDEX • • • • • • • • • • • • • • • • • • • • , • • • • • • • • • 437 ix INTRODUCTION: YING-YANG HYPOTHESIS OF IMMUNOMODULATION N,P, Plotnikoff, A,J, Murgo, R,E, Faith, and R,A, Good Oral Roberts University School of Medicine Tulsa, Oklahoma Originally the inspiration for this book stemmed from a Symposium on Enkephalins; Endorphins: Stress and the Immune System held at the Annual meeting of the American Society of Pharmacology and Experimental Therapeutics mn Philadelphia 1983, Since that meeting a significant increase in research has occurred and prompted us to compile this book. Recent research has shown that the immune system is exceedingly sensitive to the effects of enkepha1ins and endorphins. This sensitivity was illustrated by the immunodepressant effects of morphine on T-cells. In contrast the enkephalins and endorphins have shown to enhance T-cell function, At the same time a major development in this field was the discovery that the adrenal glands are the source of peripheral enkephalins and endor phins. Two major prohormones have been identified in human adrenal glands, namely, Proenkephalin A as well as proopiomelanacortin hormone. These prohormones have been shown to release various intermediate pep tide fragments(Peptide E and F) as well as the final end products. methionine enkephalin, leucine enkephalin; and beta-endorphin, Since morphine is immune depressant and is found to have high affinity for the mu and kappa receptors, it was of great interest to find that several of the prohormone peptide frag ments also has a high affinity for the same receptors, suggesting that they may also have an immuno-depressant role. In contrast the final end products methionine enkephalin and leucine enkephalin and beta-endorphin have been dis covered to be immuno-stimulant and bind preferentially to the delta and epsilon receptors, This immunomodulation by prohormone peptide fragments and enkephalin endorphin end products led to the Ying-Yang hypothesis of immunomodulation of T-cell function, We are proposing the working opioid peptide hypothesis that various prohormone fragments are released by different stressors resulting in fluctuations of immunomodu1ation in concert with the steroid hormones and the catecholamines from the adrenal glands. It is possible that a number of contradictory behavioral studies reported in the literature are a result of this immunomodulation(depression and/or stimulation) as a function of differ ential prohormone processing and type of duration of stressors. It is intriguing to consider the possibility that long term stress may result in "depletion or exhaustion phenomenon" of prohormone end products (enkephalins-endorphins) depending upon the state of behavioral coping.