Journal of the Autonomic Nervous System 81 (2000) 87–96
www.elsevier.com / locate / jans
Types of neurons in the enteric nervous system
J.B. Furness*
Department of Anatomy and Cell Biology, University of Melbourne, Parkville, VIC 3010, Australia
Abstract
This paper, written for the symposium in honour of more than 40 years’ contribution to autonomic research by Professor Geoffrey
Burnstock, highlights the progress made in understanding the organisation of the enteric nervous system over this time. Forty years ago,
the prevailing view was that the neurons within the gut wall were post-ganglionic neurons of parasympathetic pathways. This view was
replaced as evidence accrued that the neurons are part of the enteric nervous system and are involved in reflex and integrative activities
that can occur even in the absence of neuronal influence from extrinsic sources. Work in Burnstock’s laboratory led to the discovery of
intrinsic inhibitory neurons with then novel pharmacology of transmission, and precipitated investigation of neuron types in the enteric
nervous system. All the types of neurons in the enteric nervous system of the small intestine of the guinea-pig have now been identified in
terms of their morphologies, projections, primary neurotransmitters and physiological identification. In this region there are 14
functionally defined neuron types, each with a characteristic combination of morphological, neurochemical and biophysical properties.
The nerve circuits underlying effects on motility, blood flow and secretion that are mediated through the enteric nervous system are
constructed from these neurons. The circuits for simple motility reflexes are now known, and progress has been made in analysing those
involved in local control of blood flow and transmucosal fluid movement in the small intestine.  2000 Elsevier Science B.V. All rights
reserved.
Keywords: Enteric nervous system; Neurochemistry; Intestine
1. Introduction
Many of our concepts of the autonomic nervous system
derive from the work of Langley, in particular the idea that
its enteric division has characteristics that distinguish it
from the other divisions, sympathetic and parasympathetic.
Langley (1921) pointed to the large numbers of neurons in
the enteric nervous system (ENS), its degree of independence from the central nervous system, in that there
Abbreviations: ACh, acetylcholine; AHP, afterhyperpolarizing potential
that follows the action potential in AH neurons; BN, bombesin (the
mammalian form also referred to as GRP, below); CCK, cholecystokinin;
ChAT, choline acetyltransferase; CGRP, calcitonin gene related peptide;
ENK, enkephalin; ENS, enteric nervous system; EPSP, excitatory postsynaptic potential; GABA, gamma amino butyric acid; GAL, galanin;
GRP, gastrin releasing peptide (mammalian bombesin); 5-HT, 5-hydroxytryptamine; IPAN, intrinsic primary afferent neuron; MMC, migrating
myoelectric complex; NANC, non-adrenergic, non-cholinergic; NFP,
neurofilament protein; NK, neurokinin; NOS, nitric oxide synthase; NPY,
neuropeptide Y; PACAP, pituitary adenylyl cyclase activating peptide; S,
designation for enteric neurons with tetrodotoxin blocked soma action
potentials and prominent fast EPSPs; SOM, somatostatin; TK, tachykinin;
VIP, vasoactive intestinal peptide
*Tel.: 161-3-8344-5804; fax: 161-3-9347-5219.
E-mail address: john.furness@anatomy.unimelb.edu.au (J.B. Furness)
appeared to be entire reflex pathways within the ENS, and
to the relatively few efferent axons entering the gut, in
comparison to the number of enteric neurons. Surprisingly,
his ideas on the enteric nervous system faded, and by the
1950s, the majority of textbooks stated or implied that
neurons in the gut wall are parasympathetic post-ganglionic neurons.
Impetus to look afresh at the ENS came from observations in Geoff Burnstock’s laboratory in Melbourne in the
1960s, particularly the observation that transmission from
inhibitory neurons in the gut was neither adrenergic nor
cholinergic, in spite of the prevailing dogma that all
post-ganglionic transmission to final effectors could be
attributed to acetylcholine (ACh) or noradrenaline (Burnstock et al., 1963, 1964). I arrived in Geoff’s laboratory in
1967, and was quickly caught up in the excitement
generated by the discovery of non-adrenergic, noncholinergic neurons. These came to be referred to as
NANC neurons, and then as purinergic neurons, because
evidence that they may transmit by release of a purine
nucleotide was found by Geoff Burnstock and his colleagues (Burnstock, 1972).
A strong focus of the work in Geoff Burnstock’s
laboratory was the ENS, because of the initial discovery of
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J.B. Furness / Journal of the Autonomic Nervous System 81 (2000) 87 – 96
NANC neurons in the intestine. By 1980, it was clear that
the ENS contains many different neuron types, including
motor neurons to the muscle, intrinsic arterioles and
epithelium, various interneurons, and possibly intrinsic
sensory (primary afferent) neurons, although the existence
of this last type of neuron was to remain in contention for
another 15 years (see Furness et al., 1998). Functional,
pharmacological, neurochemical and morphological (light
and electron microscopy) methods had all identified a
range of neuron types. In a review published in 1980, it
was suggested that further progress in understanding the
organisation of enteric nerve circuits would depend on
bringing together the observations made with different
techniques (Furness and Costa, 1980). It was noted that
several populations of enteric neurons were defined by (at
that time) recently developed immunohistochemical methods to locate neuropeptides and it was anticipated that
immunohistochemical methods might provide an important
tool to unravel the enteric circuitry. This proved to be the
case, and immunohistochemistry combined with nerve
lesions (Furness and Costa, 1979), with electrophysiological analysis and the marking of neurons with intracellularly
injected dye (Bornstein et al., 1984), with retrograde
tracing of neuron projections (Brookes and Costa, 1990)
and with ultrastructural analysis (e.g., Pompolo and Furness, 1988; Mann et al., 1997) has been a dominant
approach in determining the organisation of enteric nerve
circuits. It is with some confidence that it can be claimed
that all classes of neuron in one region, the small intestine
of the guinea-pig, are now identified (Furness et al., 1994,
2000; Costa et al., 1996), although it is possible that some
numerically small class of neuron may remain undetected.
Seventeen types of intrinsic neurons are found, 14 of these
in the small intestine of the guinea-pig (Fig. 1 and Table
1). Some of these types can be subdivided; for example,
there are differences in chemical coding of circular muscle
motor neurons with short and long projections (Uemura et
al., 1995), and a sub-group of the intrinsic primary afferent
neurons with cell bodies in myenteric ganglia have long
anal projections (Brookes et al., 1995).
The ENS is contained within the walls of the tubular
digestive tract, pancreas and biliary system, but only the
innervation of the intestines will be considered in detail
here. The ENS has two ganglionated plexuses in the
intestine, the myenteric and submucosal plexuses, in which
almost all intrinsic nerve cells reside (Furness and Costa,
1987; Furness et al., 1999a). The myenteric plexus is
between the outer longitudinal and circular muscle layers,
and extends the full length of the digestive tract, from the
esophagus to the rectum. The submucosal plexus is
prominent only in the small and large intestines.
2. Motor neurons
In functional terms, there are five broad types, and many
subtypes, of enteric motor neuron; the five types are
Fig. 1. The types of neurons in the small intestine of the guinea-pig, all of which have been defined by their functions, cell body morphologies, chemistries
and projections. 1, Ascending interneuron; 2, myenteric intrinsic primary afferent neuron; 3, intestinofugal neuron; 4, excitatory longitudinal muscle motor
neuron; 5, inhibitory longitudinal muscle motor neuron; 6, excitatory circular muscle motor neuron; 7, inhibitory circular muscle motor neuron; 8,
descending interneuron (local reflex); 9, descending interneuron (secretomotor reflex); 10, descending interneuron (migrating myoelectric complex); 11,
submucosal intrinsic primary afferent neuron; 12, non-cholinergic secretomotor / vasodilator neuron; 13, cholinergic secretomotor / vasodilator neuron; 14,
cholinergic secretomotor (non-vasodilator) neuron. The numbers adjacent to the neurons correspond to the numbers in Table 1, which lists each of the
neuron types by their functions and provides data on the percentages of their cell bodies in the myenteric or submucosal ganglia and their chemistries. LM,
longitudinal muscle; MP, myenteric plexus; CM, circular muscle; SM, submucosal plexus; Muc, mucosa.
J.B. Furness / Journal of the Autonomic Nervous System 81 (2000) 87 – 96
89
Table 1
Types of neurons in the enteric nervous system. This table lists the neuron types that are found in the guinea-pig small intestine, some of their defining
characteristics, and percentages of occurrence in each of the ganglionated plexuses. I have also listed three types of motor neuron that are found in other
parts of the tubular digestive tract, marked by asterisks*. The numbers in parentheses are the identifying numbers for the neurons in Figs. 1 and 2
Myenteric neurons
Excitatory circular muscle
motor neurons (6)
Proportion
Chemical coding
Function / comments
12%
To all regions, primary transmitter
ACh, cotransmitter TK
Inhibitory circular muscle
motor neurons (7)
16%
Excitatory longitudinal muscle
motor neurons (4)
Inhibitory longitudinal muscle
motor neurons (5)
25%
Short: ChAT / TK / ENK /
GABA
Long: ChAT / TK / ENK / NFP
Short: NOS / VIP/ PACAP/
ENK / NPY/ GABA
Long: NOS / VIP/ PACAP/
Dynorphin / BN / NFP
ChAT / Calretinin / TK
|2%
NOS / VIP/ GABA
5%
5%
ChAT / Calretinin / TK
ChAT / NOS / VIP6
BN6NPY
ChAT / 5-HT
Ascending interneurons (local reflex) (1)
Descending interneurons
(local reflex) (8)
Descending interneurons
(secretomotor reflex) (9)
Descending interneurons (migrating
myoelectric complex) (10)
Myenteric intrinsic primary afferent
(primary sensory) neurons (2)
Intestinofugal neurons (3)
2%
N /A
ChAT / SOM
ChAT / Calbindin / TK /
NK 3 receptor
ChAT / BN / VIP/
CCK / ENK
N /A
45%
VIP/ GAL
Cholinergic secretomotor /
vasodilator neurons (13)
Cholinergic secretomotor
(non-vasodilator) neurons (14)
15%
ChAT / Calretinin /
Dynorphin
ChAT / NPY/ CCK /
SOM / CGRP/ Dynorphin
Submucosal intrinsic primary
afferent (primary sensory)
neurons (11)
*Excitatory motor neurons
to the muscularis mucosae
*Inhibitory motor neurons
to the muscularis mucosae
11%
ChAT / TK / calbindin
N /A
N /A
N /A
N /A
*Motor neurons to gut
endocrine cells
Submucosal neurons
Non-cholinergic secretomotor /
vasodilator neurons (12)
4%
26%
,1%
29%
excitatory neurons to gut muscle, inhibitory neurons to gut
muscle, secretomotor / vasodilator neurons, secretomotor
neurons that are not vasodilator and neurons innervating
entero-endocrine cells, such as those innervating the
gastrin secreting endocrine cells of the stomach (Furness et
al., 2000). The motor neurons innervating the acid secreting cells of the stomach are a special type of secretomotor
neuron; these will not be considered in detail in this
review. Three types of extrinsic motor neuron directly
innervate effectors in the gut: vagal motor neurons to the
Several cotransmitters with
varying prominence:
NO, ATP, VIP, PACAP
Primary transmitter ACh,
cotransmitter TK
Several cotransmitters with
varying prominence:
NO, ATP, VIP, PACAP
Primary transmitter ACh
Primary transmitter ACh,
ATP may be a cotransmitter
Primary transmitters ACh,
5-HT (at 5-HT 3 receptors)
Primary transmitter ACh
Primary transmitter TK
Primary transmitter ACh
For example, myenteric
neurons innervating gastrin
cells. Neurons of this type
may be in submucosal ganglia
Primary transmitter VIP. A small
proportion of these have cell
bodies in myenteric ganglia
Primary transmitter ACh
Primary transmitter ACh. A
small proportion of these have
cell bodies in myenteric ganglia
Calbindin-IR, seen with some
antisera only. Primary
transmitter assumed to be TK
Primary transmitter ACh
Pharmacology of transmission
appears to be similar
to other enteric inhibitory
muscle motor neurons
striated muscle of the esophagus (see below), noradrenergic (sympathetic) neurons that innervate gut muscle,
notably muscle of the sphincters, and noradrenergic vasoconstrictor neurons that innervate arteries within the gut
wall. There are also small numbers of noradrenergic axons
in the mucosa. Other motor effects of extrinsic nerve
pathways, such as those that reach the gut through the
vagus and pelvic nerves, and the sympathetic effects
through myenteric and submucosal ganglia, are indirect,
via enteric circuits and enteric (intrinsic) motor neurons.
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J.B. Furness / Journal of the Autonomic Nervous System 81 (2000) 87 – 96
2.1. Excitatory muscle motor neurons
All regions of the gut, and each of the muscle layers,
receive an excitatory innervation. By using effective and
specific muscarinic receptor antagonists, many investigators have shown that excitatory transmission has a
prominent muscarinic component. However, there is residual excitation that is resistant to muscarinic block. This
excitation is predominantly due to release of tachykinins
and, consistent with this, the motor neurons are immunoreactive for both the synthesizing enzyme for ACh (choline
acetyltransferase) and for tachykinins. Most antisera distinguish poorly between tachykinins; despite this, it is
generally assumed that substance P is the transmitter. It is
more likely that it is a mixture of substance P and
neurokinin A, and possibly also neuropeptides K and g
(Lippi et al., 1998). The relative roles of ACh and
tachykinins are unequal; muscarinic antagonists substantially inhibit gastrointestinal motility in vivo (Borody et
al., 1985; Galligan et al., 1986), whereas tachykinin
receptor antagonists (tested in human as possible antinociceptive drugs) have little effect. Thus acetylcholine is
the primary transmitter of excitatory muscle motor neurons.
2.2. Inhibitory muscle motor neurons
Although, with hindsight, the existence of intrinsic
inhibitory motor neurons to gut muscle (enteric inhibitory
neurons) can be deduced from work published as early as
the turn of the century (see Campbell, 1970), unequivocal
evidence for their existence came from Burnstock and his
colleagues, and from several other laboratories, notably the
¨
physiology laboratories in Goteborg,
in the late 1960s
(Burnstock, 1972; Abrahamsson, 1973). They are the
motor neurons for descending inhibitory reflexes and for
accommodation reflexes in the gut (Furness and Costa,
1973, 1987).
The enteric inhibitory neurons contain nitric oxide
synthase and release nitric oxide (NO), an observation that
has been repeatably made in many species of mammals
and in animals of other vertebrate classes. Although there
is excellent evidence that NO is a transmitter of these
neurons (Sanders and Ward, 1992; Stark and Szurszewski,
1992), it is equally clear that it is not the sole transmitter
(Makhlouf and Grider, 1993; Furness et al., 1995b). That it
is not the only transmitter can be deduced from knock out
experiments, in which the gastrointestinal tract is little
affected by the absence of NO synthase (Huang et al.,
1993) and from the incomplete block of transmission from
enteric inhibitory neurons when NO synthase is blocked,
or NO scavengers are used. The residual transmission
(which in some cases can hardly be called residual, as it is
the major component) has been variously attributed to
ATP (Burnstock, 1972; Crist et al., 1992), VIP (Fahrenkrug, 1979), PACAP (Jin et al., 1994; McConalogue et al.,
1995) and carbon monoxide (Rattan and Chakder, 1993).
It seems fairly clear that the different transmitters that are
implicated in transmission come from the same neurons,
because quantitative studies of the terminals and the cell
bodies by electron and light microscopy reveal a single
population of inhibitory neurons, immunoreactive for
NOS, VIP and PACAP (Llewellyn Smith et al., 1988;
Furness et al., 1992; Costa et al., 1996). These neurons are
subcoded in the guinea-pig small intestine; the neurons that
have short anal projections also contain GABA and NPY,
whereas longer neurons contain immunoreactivity for BN
(Uemura et al., 1995; Williamson et al., 1996). Neither
GABA, NPY nor BN have post-synaptic transmitter roles
for these neurons; this is in accord with numerous examples of chemical subcoding of autonomic neurons by
substances that do not have primary transmitter roles.
2.3. Motor neurons to the muscularis mucosae
The muscularis mucosae is innervated by both excitatory
and inhibitory motor neurons, analagous in transmission
properties to the motor neurons to the muscularis externa
(Furness and Costa, 1987). The muscularis mucosae in the
guinea-pig small intestine is very thin, and there has been
no certain identification of the locations, chemistries and
morphologies of the cell bodies that supply it. Experiments
in the dog suggest that the motor nerve supply to the
muscularis mucosae is from the submucosal plexus (Furness et al., 1990).
2.4. Motor neurons to the striated muscle esophagus
The striated muscle of the esophagus is innervated by
axons that form motor endplates, but unlike motor endplates elsewhere, individual endplates in the esophagus
receive dual innervation, one axon being from a vagal
motor neuron with its cell body in the medulla oblongata
and the other arising from a cell body in the myenteric
¨ et al., 1997). Vagal
plexus (Neuhuber et al., 1994; Worl
transmission is cholinergic, through nicotinic receptors
and, in the rat, the vagal endings are immunoreactive for
CGRP, and the endings of myenteric origin have NOS
immunoreactivity. Double staining using these markers
indicates that both fibres make synaptic connections with
the muscle, and that the two fibre types are often closely
apposed, such that they may interact presynaptically.
3. Interneurons
One type of orally directed (‘ascending’) and three types
of anally directed (‘descending’) interneuron have been
identified in the small intestine of the guinea-pig (Fig. 1,
Table 1). The ascending neurons are cholinergic and, like
J.B. Furness / Journal of the Autonomic Nervous System 81 (2000) 87 – 96
the descending neurons, form chains that extend along the
gut (Kunze and Furness, 1999). They must be the conduit
for ascending pathways that are components of the propulsive reflexes in the gut. Consistent with this is the
observation that nicotinic blocking agents, which block
fast cholinergic excitatory post-synaptic potentials (EPSPs)
at neuro-neuronal synapses in the myenteric plexus, block
ascending reflexes (Smith and Furness, 1988; Tonini and
Costa, 1990).
The three types of descending interneurons have the
following
chemical
codings:
ChAT / NOS / VIP6BN6GABA6NPY, ChAT / SOM and ChAT / 5-HT.
Studies of the connections of these neurons have led to the
hypothesis that the first type, the ChAT / NOS / VIP neurons, are involved in local motility reflexes, that the
ChAT / SOM neurons are involved in the conduction of
migrating myoelectric complexes (MMCs) in the small
intestine, and the ChAT / 5-HT neurons are involved in
secretomotor reflexes, but not directly in motility reflexes
(Pompolo and Furness, 1998; Furness et al., 2000). The
ChAT / SOM neurons are also distinctive in their morphology, having cell bodies with branching filamentous dendrites (Portbury et al., 1995; Song et al., 1997). Filamentous neurons with anally directed axons are not found
in the distal colon, and MMCs comparable to those of the
small intestine are not observed. However, in the colon
there are filamentous neurons with orally directed processes (Lomax et al., 1999). It is possible that these form
parts of ascending pathways from the pelvic nerves, that
are present in the colon, but not in the small intestine.
Pharmacological investigation of neuro-neuronal transmission in the small intestine has revealed two noncholinergic fast EPSPs, one mediated by ATP and the
other by 5-HT (Lepard et al., 1997; Zhou and Galligan,
1999). ATP transmission is in a descending pathway, but
this does not seem to be a pathway for motility control
through local reflexes (Lepard et al., 1997; Johnson et al.,
1999). Thus ATP might be a transmitter of either the
ChAT / SOM or the ChAT / 5-HT interneurons. An additional possibility is that ATP is a transmitter from a
sub-group of intrinsic primary afferent neurons (IPANs)
that have long anally directed axons (Brookes et al., 1995).
5-HT mediated transmission to myenteric neurons is
blocked by 5-HT 3 receptor antagonists (Zhou and Galligan, 1999), but the antagonists do not affect local
descending motility reflexes (Yuan et al., 1994), which
confirms the conclusion, from ultrastructural studies of
synaptic connections, that 5-HT neurons do not make
appropriate connections to be in the pathways of local
motility reflexes. On the other hand, there is evidence that
5-HT neurons are involved in secretomotor reflexes (see
Furness et al., 1999b). It is interesting that 5-HT neurons in
the distal colon, where 5-HT has also been implicated in
secretomotor pathways (Sidhu and Cooke, 1995;
Kadowaki et al., 1999), have similar morphology and
projections to those in the ileum (Wardell et al., 1994).
91
4. Intrinsic primary afferent neurons (IPANs)
Several studies have recorded reflexes in isolated intestine after extrinsic nerves supplying the intestine have been
cut and time has been allowed for their endings to
degenerate (Langley and Magnus, 1905; Crema et al.,
1970; Furness et al., 1995a). This indicates that there are
IPANs (sensory neurons) in the intestine. Direct evidence
of their identity has only been obtained in the small
intestine of the guinea-pig, where these are Dogiel type II
neurons (Kirchgessner et al., 1992; Kunze et al., 1995,
1998, 1999; Bertrand et al., 1997). Dogiel type II neurons
with similar electrophysiological properties, projections
and chemistries have been found in the large intestine of
the guinea-pig and in the rat small intestine, which
suggests that these neurons are also intrinsic sensory
neurons in other regions and species (Mann et al., 1998;
Lomax et al., 1999; Neunlist et al., 1999). The characteristic electrophysiological properties of Dogiel type II neurons of the guinea-pig ileum distinguishes them from
interneurons and motor neurons. The IPANs are AH
neurons, in which a component of the action potential is
carried by Ca 21 and a delayed and prolonged afterhyperpolarizing potential, the AHP, follows the action potential
(see Furness et al., 1998). Interneurons and motor neurons
are S neurons, most of which lack these features, but
receive large amplitude fast EPSPs, that are generally not
observed in AH neurons.
4.1. Mucosal chemosensors
Intestinal reflexes can be elicited by chemicals applied
to the lumen (Furness and Costa, 1987). Consistent with
this, experiments with isolated pieces of intestine reveal
that brief applications of small amounts of chemical
stimulants, applied to the surface of the ileal mucosa, elicit
bursts of action potentials in cell bodies of Dogiel type II
neurons in the myenteric plexus (Kunze et al., 1995;
Bertrand et al., 1997). Effective stimuli included acid (pH
3 to 5 in the supply pipette), acetic acid at neutral pH (used
as a representative short chain fatty acid) alkaline solution
and 5-HT. The neurons continued to respond when synaptic transmission was blocked by altering the bathing
solution to one containing high Mg 21 (10 mM) and low
Ca 21 (0.2 mM). Thus the responses in the IPANs are not
the consequence of their indirect activation by other
neurons.
The intrinsic sensory neurons maintain activity over
long periods of time, several hours at least, in excised
preparations in which the mucosa is present, even when
there is no stimulus applied by the experimenter (Kunze et
al., 1996). If the mucosa is removed, the activity disappears. Thus the chemical environment of the nerve
endings in the mucosa or small movements of the villi, or
both, are sufficient to stimulate the nerve endings. These
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J.B. Furness / Journal of the Autonomic Nervous System 81 (2000) 87 – 96
observations imply that IPANs are active most of the time
in the intestine in vivo.
4.2. Mucosal mechanoreceptors
Enteric reflexes are also elicited by mechanical stimuli,
such as stroking, applied to the mucosa (Hukuhara et al.,
1958; Smith and Furness, 1988; Vanner et al., 1993; Sidhu
and Cooke, 1995). The cell bodies of neurons mediating
these reflexes are possibly in both the submucosal and
myenteric plexuses. Submucosal IPANs have yet to be
recorded from directly during sensory stimulation. However, Kirchgessner et al. (1992) detected c-fos immunoreactivity in submucosal nerve cells after the mucosa had
been stimulated by puffs of nitrogen gas ejected from a
pipette. Because the c-fos expression was abolished by
tetrodotoxin, but not by the nicotinic receptor blocker,
hexamethonium, it was deduced that these were cell bodies
of IPANs that had processes in the mucosa. This assumes
that hexamethonium blocks all excitatory transmission, and
does not rule out the involvement of non-nicotinic fast
transmission or slow transmission. In a later study, styryl
dyes were used in similar experiments, and this data also
indicated that cell bodies of IPANs are in submucosal
ganglia (Kirchgessner et al., 1996). Some directly activated nerve cells were in myenteric ganglia, which is
consistent with data of Bertrand et al. (1997), suggesting
that some myenteric IPANs are sensitive to mucosal
distortion.
Reflexes that are initiated by mucosal distortion are
conducted along the intestine via the myenteric plexus
(Smith and Furness, 1988) and, consistent with this,
submucosal IPANs project to myenteric ganglia (Song et
al., 1998).
4.3. Stretch responsive neurons
It is a very old observation that enteric motility reflexes
are evoked by distension (e.g., Bayliss and Starling, 1899).
More recently, distension has been shown to cause secretomotor reflexes (Diener and Rummel, 1990; Frieling et
al., 1992). IPANs that respond to stretch would be predicted by these observations, and have been recently
recorded from directly with intracellular microelectrodes
(Kunze et al., 1998, 1999). These neurons respond tonically to tension generated by muscle contraction, and phasically to the onset of tension, or to direct distortion of their
processes (see below).
Tonic action potential firing in AH neurons was observed when stretch of the intestine was maintained at 20%
beyond its resting width, and most AH neurons were
excited by 40% stretch (Kunze et al., 1998). Smooth
muscle cells have stretch-activated channels, through
which they are excited, and contraction of muscle cells in
response to maintained stretch was necessary to elicit the
responses in IPANs. With either isoproterenol or nicar-
dipine present to prevent contraction, the sensory neurons
were not active during maintained muscle stretch of 40%
above resting length. Conversely, if the muscle was held at
its resting length, and tension was generated by addition of
the calcium channel stimulant, Bay K 8864, tension
responsive IPANs were activated (Kunze et al., 1999).
IPANs also respond to stretch without muscle contraction, because reflexes are evoked at the onset of distension
stimuli despite the muscle being paralyzed with nicardipine
(Smith et al., 1990). Consistent with this prediction, it has
been possible to retain impalements of some neurons, and
to demonstrate that they discharge action potentials when
the gut wall is stretched in the presence of nicardipine
(Kunze et al., 1999). Thus, when the intestinal wall is
rapidly stretched, the forces are effectively transmitted to
the sensory neurons, but with maintained stretch there is
buffering of the forces by connective tissue, and distortion
of the neuronal processes is not sufficient to cause their
excitation, if there is not contractile activity in the muscle.
The observation that intrinsic sensory neurons continue
to discharge when the muscle is stretched is consistent
with observations that the distended intestine generates
successive waves of peristaltic activity if distension is
maintained (Trendelenburg, 1917; Kosterlitz et al., 1956).
5. Secretomotor and vasomotor neurons
The balance of absorption and secretion of water and
electrolytes needs to be controlled in relation both to local
needs and to whole body water and electrolyte balance. To
accomplish this, there are intrinsic secretomotor neurons
controlled through local reflex circuits; these reflexes are
under strict central control, via sympathetic pathways. The
stomach also contains secretomotor neurons, those that
innervate the parietal cells, which they stimulate to release
acid, and those that innervate chief cells that release
pepsinogen. Gastric acid secretomotor neurons are
cholinergic.
Two types of intestinal secretomotor neurons, cholinergic and non-cholinergic, have been identified and, in
addition, release from the ends of IPANs in the mucosa
may have secretomotor effects (Furness et al., 2000; Fig.
2). The non-cholinergic neurons appear to mediate most of
the local reflex response, and utilise VIP, or a related
peptide, as their primary transmitter (Jodal and Lundgren,
1989; Cooke and Reddix, 1994; Reddix et al., 1994).
However, pharmacological analysis of transmission from
vasodilator neurons to the submucosal arterioles in vitro
suggest that transmission is cholinergic, despite the presence of a histochemically identified non-cholinergic innervation; no adequate explanation of this discrepancy, or
of the difference between in vivo and in vitro observations,
has been found (Vanner and Surprenant, 1996). In the
guinea-pig small intestine, there are two types of cholinergic secretomotor neuron, those that also contain NPY (and
J.B. Furness / Journal of the Autonomic Nervous System 81 (2000) 87 – 96
93
Fig. 2. Neurons with secretomotor effect in the small intestine of the guinea-pig. Functional evidence, supported by immunohistochemical data, indicates
that secretomotor effects are exerted through release from the mucosal endings of intrinsic sensory neurons (panel A) and through motor neurons, some of
which are secretomotor / vasodilator (neurons 12 and 13) and some of which are secretomotor only (neuron 14) (panel B). The numbers correspond to the
numbering of neurons in Fig. 1 and Table 1.
other peptides) and those that contain calretinin, and a
single class of non-cholinergic secretomotor neuron, immunoreactive for VIP (Fig. 2). The ACh / calretinin neurons
preferentially innervate the glands at the base of the
mucosa and have collaterals to submucosal arterioles,
whereas the ACh / NPY neurons do not appear to innervate
the arterioles. The presence of three classes of secretomotor neurons, two of which also provide vasodilator
collaterals, may provide a mechanism to balance secretion
and vasodilatation appropriate to digestive state (Furness et
al., 2000). The amount of fluid lost via the kidneys,
defecation, respiration and perspiration should be matched
by absorption from the alimentary tract. If more fluid is
absorbed with nutrients or across the gastric mucosa, some
of that can be passed back under the control of secretomotor reflexes. Thus the source of secreted fluid in the
small intestine can be a mixture of serum electrolyte and
locally absorbed electrolyte. It has been suggested that
local computation of the need for vasodilatation and local
absorption to supply electrolyte for secretion determines
the relative activation of vasodilator and non-vasodilator
secretomotor neurons (Furness et al., 2000).
A combination of data suggests that IPANs with processes in the mucosa may directly cause secretion of fluid.
The intrinsic sensory neurons are immunoreactive for
tachykinins and ChAT and their varicose processes are
immunoreactive for the vesicular acetylcholine transporter
(Li and Furness, 1998). Thus their mucosal endings could
release acetylcholine and tachykinins, both of which cause
secretion. Action potentials in one process of an IPAN
traverse the cell body to invade other processes (Hendriks
et al., 1990) and the pattern of branching of the neurons
indicates that action potentials could be conducted, as an
axon reflex, between terminals that branch within the
mucosa (Fig. 2). The secretory responses to distension and
to mucosal stroking in the guinea-pig colon are reduced by
tetrodotoxin (which blocks nerve conduction) and by
atropine (which blocks the ACh receptors on the epithelium), but not by an antagonist of cholinergic fast
neuro-neuronal transmission, mecamylamine (Frieling et
al., 1992; Sidhu and Cooke, 1995). The concentration of
mecamylamine that was used blocks nicotinic receptors in
the colon (Sidhu and Cooke, 1995). Moreover, the responses to stroking were not reduced by extrinsic denervation, indicating that they are dependent on activation of
intrinsic neurons (Cooke et al., 1997). Thus there is
sufficient evidence to postulate that acetylcholine released
from IPANs by axon reflex, or by mononeuronal reflexes
94
J.B. Furness / Journal of the Autonomic Nervous System 81 (2000) 87 – 96
crossing the IPAN soma, contributes to secretory responses.
6. Motor neurons to endocrine cells
A variety of endocrine cells reside in the mucosa of the
gastrointestinal tract, and because the mucosa is densely
innervated, most of these cells have nerve fibres in close
proximity. Functional evidence that motor neurons innervate enteric endocrine cells includes data on the control of
gastrin secretion, which is under the influence of vagal and
of intrinsic gastric pathways. The final neurons in both
paths are in the stomach wall. Transmission from the
neurons is mediated at least in part by GRP (BN). Release
from other entero-endocrine cells is also likely to be under
neural control. For example, the basal release of motilin is
reduced by atropine and tetrodotoxin, and stimulated by
muscarinic agonists, suggesting that motilin cells receive
an excitatory cholinergic input, and stimulation of the
vagus releases 5-HT from enteric endocrine cells.
7. Neuro-immune interactions
There is a wealth of data to indicate that the gut immune
system affects neurons within the gut wall, either exciting
the neurons directly or sensitising them to physiological or
pathological stimuli (Collins, 1996; Furness et al., 1999b).
In addition to immune messengers affecting neurons, there
is innervation of Peyer’s patches by enteric neurons, and
receptors for enteric neurotransmitters are located on
lymphocytes in the lamina propria of the mucosa.
8. Some comments on the circuitry
At the time that work in Geoff Burnstock’s laboratory
brought a renewed interest to studies of the ENS, almost
nothing certain was known of its intrinsic circuitry. A vast
amount of information has since been published that
allows all types of enteric neurons to be accounted for and
basic circuits for motility reflexes in the intestine to be
drawn, whereas circuits for secretomotor and vasodilator
reflexes are still inadequately described. When these are
better defined, it will be necessary to understand how
integration between the circuits occurs, because it is certain
these reflexes do not act in isolation. The circuits involve
large numbers of neurons; in a millimetre length of guineapig small intestine there are over 500 IPANs, which
communicate with each other synaptically, and several
hundred motor neurons. Thus it is necessary to incorporate
into analysis of the nerve circuits the likelihood that the
neurons act in assemblies, and that the sensory stimuli are
coded in the activities of populations of intrinsic sensory
neurons.
Acknowledgements
This work was supported by a grant from the National
Health and Medical Research Council. Heather Robbins is
thanked for her excellent assistance with the manuscript
and figures, and Dr Wolf Kunze for his discussion of the
manuscript and underlying concepts.
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