The Enteric Nervous System John Barton Furness PhD, FAA Department of Anatomy and Cell Biology, University of Melbourne, Victoria, Australia The Enteric Nervous System The Enteric Nervous System John Barton Furness PhD, FAA Department of Anatomy and Cell Biology, University of Melbourne, Victoria, Australia © 2006 John B. Furness Blackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia The right of the Author to be identifi ed as the Author of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. First published 2006 Library of Congress Cataloging-in-Publication Data Furness, John Barton. The enteric nervous system / John B. Furness. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-4051-3376-0 ISBN-10: 1-4051-3376-7 1. Gastrointestinal system--Diseases. I. Title. [DNLM: 1. Enteric Nervous System--physiology. 2. Neurons --physiology. WL 600 F988e 2006] RC817.F87 2006 616.3--dc22 2005024527 ISBN-13: 978-1-4051-3376-0 ISBN-10: 1-4051-3376-7 A catalogue record for this title is available from the British Library Set in 10/13½ Sabon by Sparks, Oxford – www.sparks.co.uk Printed and bound by Narayana Press, Odder, Denmark Commissioning Editor: Alison Brown Editorial Assistant: Saskia Van der Linden Development Editor: Rob Blundell Production Controller: Kate Charman For further information on Blackwell Publishing, visit our website: http://www.blackwellpublishing.com The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards. Contents Preface, ix Abbreviations, xi 1: Structure of the enteric nervous system, 1 The enteric plexuses, 3 Interconnections between the plexuses, 14 Extent of the ganglionated plexuses, 15 Intramural extensions of extrinsic nerves, 17 Electron microscope studies, 17 Enteric glia, 20 The structural similarities and functional differences between regions may have an evolutionary basis, 21 Development of the enteric nervous system, 23 Maturation of enteric neurons and development of function, 26 Changes in enteric neurons with aging, 27 Summary and conclusions, 28 2: Constituent neurons of the enteric nervous system, 29 Shapes of enteric neurons, 31 Cell physiological classifi cations of enteric neurons, 43 Functionally defi ned enteric neurons, 53 Neurons in human intestine with equivalence to those investigated in laboratory animals, 76 Summary and conclusions, 78 v vi CONTENTS 3: Refl ex circuitry of the enteric nervous system, 80 Evolution of ideas about enteric circuitry, 80 Motility controlling circuits of the small and large intestine, 81 Intrinsic secretomotor and vasomotor circuits, 88 Assemblies of neurons, 93 Circuits in the esophagus and stomach, 96 Co-ordination of motility, secretomotor, and vasomotor refl exes, 98 Circuits connecting the intestine, biliary system, and pancreas, 98 Sympathetic innervation of the gastrointestinal tract, 99 Summary and conclusions, 101 4: Pharmacology of transmission and sites of drug action in the enteric nervous system, 103 Chemical coding and multiple transmitters, 103 Transmitters of motor neurons that innervate the smooth muscle of the gut, 104 Transmitters at neuro-neuronal synapses, 111 Sites within the refl ex circuitry where specifi c pharmacologies of transmission can be deduced to occur, 120 Transmission from entero-endocrine cells to IPANs, 126 Roles of interstitial cells of Cajal in neuromuscular transmission, 127 Transmitters of secretomotor and vasodilator neurons, 128 Synapses in secretomotor and vasodilator pathways, 130 Transmitters of motor neurons innervating gastrin cells, 130 Summary and conclusions, 130 5: Neural control of motility, 132 Rhythmic activity of gastrointestinal muscle, 132 Structure and properties of interstitial cells of Cajal, 134 Relationship between slow wave activity and neural control, 138 Gastric motility, 140 Patterns of small intestine motility and their intrinsic neural control, 147 Motility of the colon, 157 Neural control of the esophagus, 159 Gall bladder motility, 160 Sphincters, 161 Muscle of the mucosa, 165 CONTENTS vii Mechanism of sympathetic inhibition of motility in non-sphincter regions, 166 Sympathetic innervation of the sphincters, 169 Physiological effects of noradrenergic neurons on motility in undisturbed animals, 170 Refl ex activities of sympathetic neurons that affect motility, 171 Summary and conclusions, 178 6: Enteric neurons and the physiological control of fl uid secretion and vasodilation, 180 Water and electrolyte secretion in the small and large intestines, 180 Refl ex control of water and electrolyte secretion, 182 Secretion of gastric acid, 189 Pepsinogen secretion, 194 Gastric secretion of bicarbonate, 195 Secretion into the gall bladder, 195 Pancreatic exocrine secretion, 196 Summary and conclusions, 198 7: Disorders of motility and secretion and therapeutic targets in the enteric nervous system, 200 Therapeutic endpoints for motility disorders, 201 Therapies for secretory diarrheas, 205 Enteric neuropathies involving neuronal loss or phenotypic changes, 206 Mitochondriopathies with intestinal manifestations, 207 Irritable bowel syndrome and plasticity of enteric neurons, 208 Summary and conclusions, 210 Epilogue: the future of enteric neurobiology, 211 References, 214 Index, 267 Preface The enteric nervous system is of special interest because it is the only sub- stantial grouping of neurons outside the central nervous system that form circuits capable of autonomous refl ex activity. In humans it contains around 500 million neurons that fall into about 20 functional classes. Because of its size, complexity, and certain structural similarities, it has been likened to a second brain. Although the enteric nervous system was discovered almost 150 years ago, and several remarkably insightful hypotheses about its functions were made in the 19th century, a long period ensued in which progress was mea- gre in comparison to the effort made, because methods available were not adequate to determine the intrinsic circuitry of the enteric nervous system and the properties of its constituent neurons. In the last 20–30 years, new tech- niques, and excellent application of such techniques, have provided a wealth of information on the structural complexity, neuron types, and connectivity of the enteric nervous system and on the transmitters and cell physiology of enteric neurons. Beginning at an earlier time, and proceeding in parallel, have been investigations of the patterns of movement and secretory functions of the digestive tract, and their control. This book aims to integrate the detailed cellular knowledge of the enteric nervous system with the more macroscopic information that is provided by physiological studies of organs, especially in the living animal or human. In doing so, I have tried to deal with the emergence of knowledge in historical perspective, where possible by drawing on early information to acknowledge the contributions made by pioneers of enteric neurobiology, and in places to reproduce original illustrations from early publications. I hope that the reader will enjoy this approach. I have also created many new illustrations, especially of the organization of enteric nerve circuits, which I hope will pro- vide an understanding of the enteric nervous system that the written word cannot easily convey. The fi rst four chapters lay the groundwork, by dealing with the structure of the enteric nervous system, the defi ning cell physiological, morphological, ix x PREFACE and neurochemical properties that allow its neurons to be functionally clas- sifi ed, the enteric neurotransmitters and the intrinsic nerve circuits within the alimentary tract. This is followed by two chapters on gastrointestinal physiol- ogy, fi rst on the contractile activity of the muscular walls of the digestive tract and the second on secretory function. In these two chapters I try to develop an understanding of the roles of enteric neurons and how they perform these roles. I have also sought to relate control through enteric circuits to control exerted by the vagus and the sympathetic innervation of the digestive organs, and to a lesser extent through the pelvic nerves. The involvement of altered structure and function of the enteric nervous system in some disease states is well recognized. Nevertheless, how to use the new-found knowledge of the enteric nervous system to understand the rela- tions between changes in the neurons and clinical manifestations of disease is a challenge. Moreover, how the neurons might be manipulated by thera- peutic compounds to ameliorate disorders of the digestive system is elusive, in many cases. The problems of understanding and treating digestive diseases that involve the enteric nervous system, or functions controlled by the enteric nervous system, are