PhD, FAA
Department of Anatomy and Cell Biology,
University of Melbourne, Victoria,
Australia

© 2006 John B. Furness
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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: 978-1-4051-3376-0
ISBN-10: 1-4051-3376-7
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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

The enteric nervous system is of special interest because it is the only substantial 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 meagre 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 techniques, 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 provide 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 classifi ed, the enteric neurotransmitters and the intrinsic nerve circuits within the alimentary tract. This is followed by two chapters on gastrointestinal physiology, 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 relations between changes in the neurons and clinical manifestations of disease is a challenge. Moreover, how the neurons might be manipulated by therapeutic 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 interpretation 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 Schemann, Dr Keith Sharkey, Dr Henrik Sjövall, Dr Werner Stach, who provided previously unpublished micrographs, Dr Jean-Pierre Timmermans, Dr Marcello 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 understanding 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 Furness
Melbourne, May 2005

AC, adenylyl cyclase
ACh, acetylcholine
AChE, acetylcholine esterase
ADP, after-depolarizing potential
AH, designation of neurons having slow after-hyperpolarizing potentials
AHP, after-hyperpolarizing potential
AMP, adenosine monophosphate
AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
AP, action potential
ATP, adenosine triphosphate
BK, large-conductance potassium channel
BMP, bone morphogenic protein
BN, bombesin (the mammalian form also referred to as GRP, below) cAMP, cyclic adenosine monophosphate
CCK, cholecystokinin
CFTR, cystic fi brosis transmembrane conductance regulator
CGRP, calcitonin gene-related peptide
ChAT, choline acetyltransferase
CM, circular muscle
CNS, central nervous system
DAG, diacyl glycerol
DMP, deep muscular plexus
DMPP, dimethyl phenyl piperazinium
DYN, dynorphin
ECL, enterochromaffi n-like (cell)
EJP, excitatory junction potential
ENK, enkephalin
E PSP, excitatory post-synaptic potential
GABA, γ-aminobutyric acid
GAL, galanin gCa v
, voltage-sensitive calcium conductance gK
Ca
, Ca
2+ -dependent K + conductance gNa v
, voltage-dependent Na + conductance
GRP, gastrin-releasing peptide (also known as mammalian bombesin) xi

xii ABBREVIATIONS
Gs, stimulating G-protein
5-HT, 5-hydroxytryptamine (serotonin)
HCN, hyperpolarization activated non-specifi c cation conductance
HVA, high-voltage activated calcium current
I
AHP
, AHP current
IBS, irritable bowel syndrome
I
Ca v
, voltage-sensitive calcium current
ICC, interstitial cell(s) of Cajal
I h, hyperpolarization-activated cation current
IK, intermediate-conductance potassium channel
I
K
ATP
, ATP-dependent potassium current
IPAN, intrinsic primary afferent neuron
IPSP, inhibitory post-synaptic potential
LM, longitudinal muscle
MAP2, microtubule associated protein 2
MELAS, multisystem mitochondriopathy
MMC, migrating myoelectric complex
MNGIE, mitochondrial neurogastrointestinal encephalomyopathy
MP, membrane potential
Muc, mucosa
L
-NAME,
L
-nitro-arginine methyl ester nAChRs, nicotinic acetylcholine receptors
NANC, non-adrenergic, non-cholinergic
NFP, neurofi lament protein
Nic, nicotinic
NK, neurokinin
NO, nitric oxide
NOS, nitric oxide synthase
NPY, neuropeptide tyrosine, usually known as neuropeptide Y
P
2X
P
2Y
, purine receptor 2X
, purine receptor 2Y
PACAP, pituitary adenylyl cyclase activating peptide
PCR, polymerase chain reaction
PDBu, phorbol dibutyrate
PHI, peptide histidine isoleucine
PHM, peptide histidine methionine
PKA, protein kinase A
PKC, protein kinase C
PLC, phospholipase C
PPADS, pyridoxal-phosphate-6-azophenyl-2΄,4΄-disulfonic acid
PVG, prevertebral ganglion
PYY, peptide tyrosine tyrosine
Rin, input resistance
RT, room temperature
SAC, stretch activated channel
SGLT1, Na + /glucose co-transporter 1
SK, small-conductance potassium channel

ABBREVIATIONS xiii
SM, submucosa
SOM, somatostatin
SSPE, sustained slow post-synaptic potential
STC, slow-transit constipation
TEA, tetraethylammonium
TK, tachykinin
TRH, thyrotropin-releasing hormone
TTX, tetrodotoxin
TTX-R
I
Na
V
, TTX-resistant sodium current
VIP, vasoactive intestinal peptide
VPAC, vasoactive intestinal peptide; pituitary adenylyl cyclase activating peptide