Autonomic and Enteric Ganglia Transmission and Its Pharmacology Autonomic and Enteric Ganglia Transmission and Its Pharmacology Edited by Alexander G. Karczmar Loyola University Stritch School of Medicine Maywood. Illinois Kyozo Koketsu and Syogoro Nishi Kurume University School of Medicine Kurume. Japan PLENUM PRESS • NEW YORK AND LONDON Library of Congress Cataloging in Publication Data Main entry under title: Autonomic and enteric ganglia. Includes bibliographies and index. 1. Ganglia, Autonomic. 2. Neural transmission. 3. Ganglionic blocking agents. 4. Ganglionic stimulating agents ..I . Karczmar, A. G. (Alexander George), 1918- . II. Koket su, Kyozo, 1922- . III. Nishi, Syogoro. [DNLM: 1. Ganglia, Autonomic-physiology. 2. Ganglionic Blockaders-pharmacodynamics. 3. Gastrointestinal System-innervation. 4. Neural Transmission. 5. Neuroregulators-pharmacodynamics. WL 600 A9388j QP368.8.A96 1985 612'.89 85-19398 ISBN-13: 978-1-4615-9438-3 © 1986 Plenum Press. New York Soft cover reprint of the hardcover I st edition 1973 A Division of Plenum Publishing Corporation 233 Spring Street, New York, N.Y. 10013 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, ISBN-13: 978-1-4615-9438-3 e-ISBN-13: 978-1-4615-9436-9 DOl: 10 .1 0071 978-1-4615-9436-9 Foreword In the early 1960s, Dr. Alexander G. Karczmar, Professor of Pharmacology and Experimental Therapeutics at the Stritch School of Medicine of the Medical Center at Loyola University of Chicago, was confronted with a certain technical problem concerning his studies of synaptic transmission by means of microelectrode methods. He thought that the problem might be resolved if he could interest a microelectrode expert such as Dr. Kyozo Koketsu in his studies. Dr. Koketsu was a past member of the Faculty of the Kurume University School of Medicine who as a Research Fellow at the Australian National University had helped Sir John Eccles, subse quently a Nobel Prize winner, in developing microelectrode procedures. After further considering the matter, Dr. Karczmar was pleasantly sur prised to discover that by coincidence Dr. Koketsu was his neighbor, serving at that time as a Research Professor at the Neuropsychiatry Institute of the University of Illinois, College of Medicine of Chicago. This was the beginning of a long relationship, as Dr. Koketsu joined Dr. Karczmar at Loyola as Professor of Pharmacology and Therapeutics and Director of the Neurophysiology Laboratory at the Stritch School of Medicine. It was not long before Dr. Syogoro Nishi-Dr. Koketsu's former colleague on the Faculty of Medicine at Kurume University, and at that time a Research Fellow in Neurophysiology at the Rockefeller Institute in New York joined Drs. Koketsu and Karczmar at Loyola. Although in due time Drs. Nishi and Koketsu returned to their alma mater (where Dr. Nishi is today a Professor of Physiology and Dr. Koketsu is Dean and President of the Kurume University School of Medicine), the friendship and teamwork of these three men lasted beyond their time together at Loyola and continues today. Working together, Drs. Karczmar, Koketsu, and Nishi established at the Stritch School of Medicine a nucleus of synaptic (including ganglionic) researchers, and their laboratories became the center of activities for their students, research associates, postdoctoral fellows, and visiting investi- v vi Foreword gators. Among the members of their team were scientists from Europe (including Poland, France, Russia, England, and Scotland), Australia, Ja pan, and China. And the research in these truly international laboratories led to many discoveries that helped clarify processes of synaptic trans mission that constitute the basis of CNS function and behavior. After the return of Drs. Koketsu and Nishi to Japan, the research and training ac tivities of what then became a Loyola-Kurume group were continued, and there was a continuous exchange of personnel between Kurume and Chicago. This book is a result of these many years of friendship and teamwork, as the editors of this book-which I trust is both unique and remark able-and the authors are men and women who have worked together, whether at Loyola or Kurume. As the Provost of the Medical Center of Loyola University of Chicago, I am pleased to recall this history of research and training development involving both this Center and Kurume University Medical School. I am happy that Loyola University Medical Center contributed to the support of the investigations of Drs. Karczmar, Koketsu and Nishi, and of their associates. Similarly, we were happy to provide all the help we could during the planning session for this book and during its final preparation. I know that this book constitutes only one stage in the research and training activities of Kurume University School of Medicine-Loyola Uni versity Medical Center, and that more papers and texts will result in the future from this notable international cooperation. Richard W. Matre, Ph.D. Provost Loyola University Medical Center Maywood, Illinois Preface This book was planned by the editors with a specific aim and a defined philosophy. The aim was to describe the transmission processes and re lated phenomena in vertebrate autonomic and enteric ganglia; the phi losophy was to present the pertinent information as a unified whole, with as focused an approach as possible, avoiding any degree of tangentiality, even at the risk of occasional incompleteness. There was an additional aspect to this book: It was to be authored by a team of friends of long standing who were in a good position to prepare a cohesive, homogeneous text, since they had been co-workers for many years in ganglionic research and had published many papers and reviews together. Once the book's philosophy and aims had been decided on by the editors, its plan could be laid down almost automatically and its chapters assigned as appropriate for the interests and research experience of the members of the team. First of all, it appeared self-evident that to render ganglionic transmission and its processes intelligible, an understanding of the anatomy, electrophysiology, and neuropharmacology of autonomic and enteric ganglia was needed. Accordingly, this book emphasizes the anatomy, histology, and cytology as well as the cytochemistry of the sym pathetic and parasympathetic ganglia and of the enteric neurons. With this as the substrate for the dynamic events of autonomic ganglionic and enteric transmission, the characteristics of the membranes involved in this transmission are described. The responses, both pre- and postsyn aptic, of the ganglionic and enteric membranes are described in detail, as are the electrophysiological characteristics of these responses and their ionic generation. The transmitters involved in the various responses and their presynaptic or intraneuronal origin, the release mechanisms, and the postsynaptic sites of their action are also discussed. Furthermore, the molecular bases of these responses-the receptors and the channels-are described. Thus, the concepts of ganglionic and/or enteric nicotinic, mus- vii viii Preface carinic, and peptidergic transmission are explored in terms of their gen eration, electrophysiology, and types of responses. To this end, attention is focused on bioactive substances, whether active as endogenous trans mitters and modulators or as exogenous substances that affect the ganglia pre- or postsynaptically when applied to the ganglia. Thus, this topic merges with a consideration of the pharmacology of ganglionic transmis sion. Furthermore-since it is clear that endogenous bioactive substances as well as pharmacological agents ultimately affect the ganglia via certain energy processes that they generate-the role of second messengers in the generation of ganglionic potentials is considered. The numerous refer ences in this text to the many substances known today as transmitters and putative transmitters-such as histamine, catecholamines, serotonin, GABA and other amino acids, bioactive peptides including substance P and enkephalins, and, of course, acetylcholine as well as second messen gers (cyclic nucleotides and the components of the phosphatidylinositol cycle)-reflect the concept, first enunciated in the eighteenth century, that ganglia constitutes "little brains." In fact, one chapter in this book con cerns the ganglia as a convenient model for the study of the CNS. Finally, it was necessary to include a discussion of the presynaptic spinal neurons and reflexes, including the afferent cells, since the ganglia and the enteric system are activated preganglionically at the afferent end of the reflex. In this same context, it was important to cover physiological aspects of transmission, particularly in organs endowed with as much autonomic peripheral control as the neurons of the enteric system, in cluding ascending and decending excitations and inhibitions. On the other hand, to achieve the desired focus, the editors decided that such subjects as embryonic development of the ganglia and the enteric system, ganglionic metabolism, invertebrate ganglia, and the physiology and pharmacology of effector organs did not belong in this book. Nor does this book include descriptions of specific research topics. Yet, within this entity, there is complexity, as behooves the "little brains." The full significance of this complexity and of the "little brain" concept gradually became apparent in the course of ganglionic and enteric studies beginning during the nineteenth century. The historical devel opment and emergence of this concept, presented in the first chapter of this book, not only provide an exciting insight into the heuristic thinking and experimental elegance of the work of our predecessors-such as Lang ley and Dale; Feldberg, Kibjakow, and MacIntosh; and Eccles, Biilbring, and Zamis-but also serve to clarify the components of this complexity. In addition, Chapter 3 seeks to define and classify the various processes and their interactions that bring about point-to-point control of ganglionic and enteric transmission, and to provide a bird's-eye view of the current status of concepts of ganglionic transmission and its multifactorial regulation. Who may benefit from reading this book? Since mathematical, bio- Preface ix physical, and transmitter aspects of membrane function and ganglionic potentials and their generation are described in some detail, synaptologists and other neuroscientists should be included among its readers. Since the ganglia clearly exemplify the processes of synaptic transmission and of their modulation-processes that cannot be as easily analyzed in the CNS neurologists should also profit from reading this volume. Furthermore, since this book concerns the classic subject of autonomic and enteric transmission, pharmacologists of any ilk should find some interest and pleasure in perusing these chapters. By the same token, clinicians who are concerned with several aspects of autonomic disease and do not as yet forego the hope that hypertension may one day be treated pharma cologically might be interested in paging through this book. Finally, medical students should look to this book for basic descriptions of syn aptic mechanisms, transmitter function, peristaltic motion, and gastro intestinal processes. We would be remiss if we did not at this time express our thanks to the many people who contributed to the creation of this volume. The editors wish to include in this list, of course, our colleagues, who with us are the authors. We should also thank our staffs, which include Mary Ann Jurgus in Chicago and Blockaden Machen in Kurume. Also, our thanks are due to the administrations of Loyola University of Chicago and its Stritch School of Medicine and of Kurume University Medical College, who made our past research as well as this endeavor possible. Special thanks are due to Dr. Charles Visokay of Karger Publishers, who helped us in organizing the planning sessions, and to Mr. Kirk Jensen, Senior Editor of Plenum Publishing Corporation, and his firm for their help and for their patience and support during the long process of creating and producing this book. Alexander G. Karczmar, K. Koketsu, and S. Nishi Maywood, Illinois, and Kurume, Japan Contents I. mSTORY AND ANATOMICAL BASES OF GANGLIONIC AND ENTERIC TRANSMISSION Chapter 1. Historical Development of Concepts of Ganglionic Transmission 3 Alexander G. Karczmar I. Anatomical and Morphological Aspects of Past Ganglionic Research 3 II. Neurotransmitters 9 III. Neuropharmacology and Neurophysiology 15 IV. Unanswered Questions 17 References 18 Chapter 2. Anatomy, Histology, and Electron Microscopy of Sympathetic, Parasympathetic, and Enteric Neurons 27 Gordon M. Lees I. Introduction 27 II. Parasympathetic and Sympathetic Ganglia 28 A. Gross Anatomical Considerations 28 B. Convergence and Divergence 30 C. Origin of Fibers That Form Postganglionic Nerves from Superior Cervical Ganglia 32 D. Innervation of the Gallbladder 34 E. Innervation of the Urinary Bladder 34 F. Ultrastructural Considerations of Principal Sympathetic Ganglion Cells 35 III. Chromaffin Cells. Small Intensely Fluorescent Cells. Small Granule-Containing Cells. Interneurons. Paraneurons. and Paraganglia 37 IV. Enteric Nervous System 39 A. Extrinsic Nerves 39 B. Intrinsic Nerves 41 C. Glial Cells 47 V. Peptides in Other Autonomic Ganglia 48 References 50 xi