The Enteric Nervous System

The Enteric Nervous System

John Barton FurnessPhD, FAADepartment of Anatomy and Cell Biology,University of Melbourne, Victoria,Australia

© 2006 John B. FurnessBlackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USABlackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UKBlackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia

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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: 978-1-4051-3376-0ISBN-10: 1-4051-3376-7

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v

Contents

Preface, ix

Abbreviations, xi

1: Structure of the enteric nervous system, 1

The enteric plexuses, 3Interconnections between the plexuses, 14Extent of the ganglionated plexuses, 15Intramural extensions of extrinsic nerves, 17Electron microscope studies, 17Enteric glia, 20The structural similarities and functional differences between regions may

have an evolutionary basis, 21Development of the enteric nervous system, 23Maturation of enteric neurons and development of function, 26Changes in enteric neurons with aging, 27Summary and conclusions, 28

2: Constituent neurons of the enteric nervous system, 29

Shapes of enteric neurons, 31Cell physiological classifi cations of enteric neurons, 43Functionally defi ned enteric neurons, 53Neurons in human intestine with equivalence to those investigated in

laboratory animals, 76Summary and conclusions, 78

v i CONTENTS

3: Refl ex circuitry of the enteric nervous system, 80

Evolution of ideas about enteric circuitry, 80Motility controlling circuits of the small and large intestine, 81Intrinsic secretomotor and vasomotor circuits, 88Assemblies of neurons, 93Circuits in the esophagus and stomach, 96Co-ordination of motility, secretomotor, and vasomotor refl exes, 98Circuits connecting the intestine, biliary system, and pancreas, 98Sympathetic innervation of the gastrointestinal tract, 99Summary and conclusions, 101

4: Pharmacology of transmission and sites of drug action in the enteric nervous system, 103

Chemical coding and multiple transmitters, 103Transmitters of motor neurons that innervate the smooth muscle of the

gut, 104Transmitters at neuro-neuronal synapses, 111Sites within the refl ex circuitry where specifi c pharmacologies of transmission can be deduced to occur, 120Transmission from entero-endocrine cells to IPANs, 126Roles of interstitial cells of Cajal in neuromuscular transmission, 127Transmitters of secretomotor and vasodilator neurons, 128Synapses in secretomotor and vasodilator pathways, 130Transmitters of motor neurons innervating gastrin cells, 130Summary and conclusions, 130

5: Neural control of motility, 132

Rhythmic activity of gastrointestinal muscle, 132Structure and properties of interstitial cells of Cajal, 134Relationship between slow wave activity and neural control, 138Gastric motility, 140Patterns of small intestine motility and their intrinsic neural control, 147Motility of the colon, 157Neural control of the esophagus, 159Gall bladder motility, 160Sphincters, 161Muscle of the mucosa, 165

v i iCONTENTS

Mechanism of sympathetic inhibition of motility in non-sphincterregions, 166

Sympathetic innervation of the sphincters, 169Physiological effects of noradrenergic neurons on motility in undisturbed

animals, 170Refl ex activities of sympathetic neurons that affect motility, 171Summary 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, 180Refl ex control of water and electrolyte secretion, 182Secretion of gastric acid, 189Pepsinogen secretion, 194Gastric secretion of bicarbonate, 195Secretion into the gall bladder, 195Pancreatic exocrine secretion, 196Summary and conclusions, 198

7: Disorders of motility and secretion and therapeutic targets in the enteric nervous system, 200

Therapeutic endpoints for motility disorders, 201Therapies for secretory diarrheas, 205Enteric neuropathies involving neuronal loss or phenotypic changes, 206Mitochondriopathies with intestinal manifestations, 207Irritable bowel syndrome and plasticity of enteric neurons, 208Summary and conclusions, 210

Epilogue: the future of enteric neurobiology, 211References, 214Index, 267

ix

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,

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 touched on throughout the book, and are specifi cally discussed in Chapter 7.

In writing this book I have relied on the assistance and advice of many colleagues who have generously read and commented on parts of book, in some cases through several drafts. My special thanks go to Dr Paul Andrews, Dr Joel Bornstein, Dr Axel Brehmer, who also helped me with the interpreta-tion of some of the older literature published in German, Dr Nadine Clerc, Dr Helen Cox, Dr Roberto de Giorgio, Dr Giorgio Gabella, Dr Peter Holzer, Dr Terumasa Komuro, Dr Alan Lomax, Dr Kulmira Nurgali, Dr Michael Sche-mann, Dr Keith Sharkey, Dr Henrik Sjövall, Dr Werner Stach, who provided previously unpublished micrographs, Dr Jean-Pierre Timmermans, Dr Mar-cello Tonini and Dr Heather Young. For assistance in the preparation of the illustrations I am very grateful to Melanie Clarke, Anderson Hind, and Trung Nguyen, and for editorial help and assistance with the references, to Emma James. I would also like to thank the many colleagues who gave permission for illustrations to be included in the book.

I hope that this book succeeds in linking the extensive knowledge of the structure and cell physiology of the enteric nervous system to an understand-ing of digestive physiology, and that in so doing it helps provide a rational basis for therapeutic intervention, and even reasons why some interventions may fail.

I enjoyed writing the book, although at times it was a hard task. I hope that in reading the book you encounter only the enjoyment.

John B FurnessMelbourne, May 2005

x i

Abbreviations

AC, adenylyl cyclaseACh, acetylcholineAChE, acetylcholine esteraseADP, after-depolarizing potentialAH, designation of neurons having slow after-hyperpolarizing potentialsAHP, after-hyperpolarizing potentialAMP, adenosine monophosphateAMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidAP, action potentialATP, adenosine triphosphateBK, large-conductance potassium channelBMP, bone morphogenic proteinBN, bombesin (the mammalian form also referred to as GRP, below)cAMP, cyclic adenosine monophosphateCCK, cholecystokininCFTR, cystic fi brosis transmembrane conductance regulatorCGRP, calcitonin gene-related peptideChAT, choline acetyltransferaseCM, circular muscleCNS, central nervous systemDAG, diacyl glycerolDMP, deep muscular plexusDMPP, dimethyl phenyl piperaziniumDYN, dynorphinECL, enterochromaffi n-like (cell)EJP, excitatory junction potentialENK, enkephalinEPSP, excitatory post-synaptic potentialGABA, γ-aminobutyric acidGAL, galaningCav, voltage-sensitive calcium conductancegK

Ca, Ca2+-dependent K+ conductancegNav, voltage-dependent Na+ conductanceGRP, gastrin-releasing peptide (also known as mammalian bombesin)

x i i ABBREVIATIONS

Gs, stimulating G-protein5-HT, 5-hydroxytryptamine (serotonin)HCN, hyperpolarization activated non-specifi c cation conductanceHVA, high-voltage activated calcium currentIAHP , AHP currentIBS, irritable bowel syndromeICav, voltage-sensitive calcium currentICC, interstitial cell(s) of CajalIh, hyperpolarization-activated cation currentIK, intermediate-conductance potassium channelIKATP , ATP-dependent potassium currentIPAN, intrinsic primary afferent neuronIPSP, inhibitory post-synaptic potentialLM, longitudinal muscleMAP2, microtubule associated protein 2MELAS, multisystem mitochondriopathyMMC, migrating myoelectric complexMNGIE, mitochondrial neurogastrointestinal encephalomyopathyMP, membrane potentialMuc, mucosaL-NAME, L-nitro-arginine methyl esternAChRs, nicotinic acetylcholine receptorsNANC, non-adrenergic, non-cholinergicNFP, neurofi lament proteinNic, nicotinicNK, neurokininNO, nitric oxideNOS, nitric oxide synthaseNPY, neuropeptide tyrosine, usually known as neuropeptide YP2X, purine receptor 2XP2Y, purine receptor 2YPACAP, pituitary adenylyl cyclase activating peptidePCR, polymerase chain reactionPDBu, phorbol dibutyratePHI, peptide histidine isoleucinePHM, peptide histidine methioninePKA, protein kinase APKC, protein kinase CPLC, phospholipase CPPADS, pyridoxal-phosphate-6-azophenyl-2΄,4΄-disulfonic acidPVG, prevertebral ganglionPYY, peptide tyrosine tyrosineRin, input resistanceRT, room temperatureSAC, stretch activated channelSGLT1, Na+/glucose co-transporter 1SK, small-conductance potassium channel

x i i iABBREVIATIONS

SM, submucosaSOM, somatostatinSSPE, sustained slow post-synaptic potentialSTC, slow-transit constipationTEA, tetraethylammoniumTK, tachykininTRH, thyrotropin-releasing hormoneTTX, tetrodotoxinTTX-R INaV, TTX-resistant sodium currentVIP, vasoactive intestinal peptideVPAC, vasoactive intestinal peptide; pituitary adenylyl cyclase activating

peptide