Am J Physiol Gastrointest Liver Physiol 283: G1217–G1225, 2002.
First published July 31, 2002; 10.1152/ajpgi.00249.2002.
themes
Musings on the Wanderer: What’s New in Our
Understanding of Vago-Vagal Reflexes?
I. Morphology and topography of vagal afferents
innervating the GI tract
Powley, Terry L., and Robert J. Phillips. Musings on
the Wanderer: What’s New in Our Understanding of VagoVagal Reflexes? I. Morphology and topography of vagal afferents innervating the GI tract. Am J Physiol Gastrointest
Liver Physiol 283: G1217–G1225, 2002. First published July
31, 2002; 10.1152/ajpgi.00249.2002.—An understanding of
the events initiating vago-vagal reflexes requires knowledge
of mechanisms of transduction by vagal afferents. Such
information presumes an understanding of receptor morphology and location. Anatomic studies have recently characterized two types of vagal afferents, both putative mechanoreceptors distributed in gastrointestinal (GI) smooth muscle.
These two receptors are highly specialized in that they 1) are
morphologically distinct, 2) have different smooth muscle
targets, 3) form complexes with dissimilar accessory cells,
and 4) vary in their regional distributions throughout the GI
tract. By comparison, information on the architecture and
regional distributions of other classes of vagal afferents,
notably chemoreceptors, has only begun to accumulate.
Progress on the study of the two mechanoreceptors, however,
illustrates general principles and delineates experimental
issues that may apply to other submodalities of vagal afferents. By extension from morphological and physiological observations on the two species of smooth muscle endings, it is
reasonable to hypothesize that additional classes of vagal
receptors are also differentiated morphologically and that
they vary in structure, accessory cells, regional distributions,
and other features. A full appreciation of vago-vagal reflexes
will require thorough structural and regional analyses of
each of the types of vagal receptors within the GI tract.
chemoreceptors; mechanoreceptors; transduction; vagus; visceral afferents
(GI) vago-vagal reflexes are initiated
when vagal afferents transduce energy associated with
events in the gut. Transduction is the process in which
a receptor, that is a first-order afferent or an accessory
GASTROINTESTINAL
Address for reprint requests and other correspondence: T. L. Powley, 165 Peirce Hall, Purdue Univ., West Lafayette, IN 47907
(E-mail: [email protected]).
http://www.ajpgi.org
cell that interacts with such an afferent, translates
energy from a stimulus into electrical signals that can
be propagated by the nervous system. As the definition
implies, studies of transduction in visceral afferents
need to specify the receptor, the stimulus energy, and
the resulting cellular signaling events. Even though
the structural complexities of the gut and the resulting
difficulties in achieving spatial and temporal stimulus
control within the GI tract make refined study of its
interoceptors difficult, a consideration of the formal
elements of the definition of transduction serves to
focus some key issues.
Besides the definition of transduction, other lessons
from recent progress in elucidating other afferent systems also offer useful perspective on the analysis of
vago-vagal reflexes. In particular, the breakthroughs
of the last two decades in understanding transduction
in other afferent systems (e.g., vision, audition, olfaction, taste) have involved isolating and characterizing
the receptor cell and the site of stimulation, specification of the energetic event that is translated to a neural
signal, cloning of the membrane-bound receptors, and
identification of the second-messenger pathways (cf.
Ref. 30). For each of the well-characterized senses,
advances have occurred by an iterative series of complementary and parallel observations specifying more
precisely the receptor and the stimulus. Then, after the
receptor has been thoroughly delineated and the stimulus energy accurately characterized, the membrane
events and intracellular signaling pathways have been
identified.
STRUCTURE/FUNCTION ANALYSES
In the case of vago-vagal reflexes and the afferents
that initiate them, research has commonly focused on
the stimulus, with less attention given to the receptor
side of the equation. Vago-vagal reflexes have been
conventionally studied by delivering mechanical or
chemical stimuli to the luminal surface of the gut.
When integrative reflexes have been the focus of the
0193-1857/02 $5.00 Copyright © 2002 the American Physiological Society
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TERRY L. POWLEY AND ROBERT J. PHILLIPS
Department of Psychological Sciences, Purdue University, West Lafayette, Indiana 47907
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defense, and vascular perfusion as well as behaviors
such as food intake and toxin avoidance. The extent
and the irony of the problem that structural studies of
receptors in this extensive body surface have been
neglected in GI physiology are both underscored by the
observation that more structural work is available on
the electroreceptors found in electric fish (and, for that
matter, on several other exotic classes of receptors
from the annals of zoology) than on the vagal receptors
in the GI tract.
Recently, however, some progress has been made in
characterizing vagal afferents in terms of structural/
functional considerations, and examples of this progress are summarized below. Some of the implications of
a fuller characterization of the receptor are also discussed here.
VAGAL AFFERENT SUBMODALITIES
For many species, anatomic surveys have not yet
established the size of the afferent pool supplied to the
gut by the vagus. As a general index, however, the
abdominal vagus of the rat has ⬃16,250 afferents and,
by comparison, ⬃6,000 efferents (22). Since most of the
vagal projections in the abdomen are to the GI tract,
these figures are likely to be good estimates of the total
pool of vagal fibers found in the gut. Given that the
nodose ganglion, the source of the afferent fibers, does
not display exceptional changes in numbers of perikarya across species that have been evaluated, the
number of vagal afferents to the GI tract in the rat may
be a reasonable approximation for other species as
well. Regionally, vagal afferent endings are most
densely distributed in the proximal GI tract (esophagus, stomach, and small intestine), although they are
located throughout the length of the gut (31). A comparison of the relatively modest number of vagal afferents innervating the gut and the extensive mass and
surface area of the GI tract (cf. Ref. 8) suggests that
individual fibers would be expected to branch extensively and to produce multiple endings within their
target sites. This prediction holds for the two vagal
afferents to the GI tract for which we have the most
structural information (see VAGAL MECHANORECEPTORS).
Electrophysiological as well as physiological experiments have established that most of these afferents
appear to be either mechano- or chemoreceptors, and
most of the work on vago-vagal reflexes has focused on
these two submodalities. Although other submodalities
(e.g., thermoreceptors) have also been described (e.g.,
Ref. 13), little if anything is known about the mechanisms of transduction in these additional types of
endings, and they will not be covered in the present
survey. A preponderance of vagal fibers relay lowthreshold mechano- or chemoreceptor signals associated with the movement and digestion of nutrients. In
the distal bowel, innervation from dorsal root visceral
afferents predominates and a preponderance of these
fibers are involved in detecting high-threshold mechanical or nociceptive events (28). These nonvagal,
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work, the circuitry and its functions have been typically inferred from physiological and/or behavioral responses. When transduction events have been the
focus, the operations of vagal afferents have been inferred from extracellular or intracellular recordings of
nodose ganglion neurons. In both strategies, emphasis
has been most frequently on the stimulus and responses in the circuit but not on the receptor. By
applying incrementally smaller stimuli to progressively more restricted sites, by minimizing the latencies between stimulation and a detectable response, by
employing variations in the molecular structure or the
configuration of the stimuli, by employing blockers and
nerve cuts to delimit the mechanism, and by using
other reductionistic strategies, this approach works to
specify the effective stimulus, where and how it works,
and how many steps may be involved in converting a
GI stimulus into a response. This strategy has been
used in a number of highly innovative experiments and
has made significant progress in identifying some of
the effective (and ineffective) stimuli that directly, or
indirectly, initiate vago-vagal reflexes. These experiments have been reviewed in recent papers in this
journal (e.g., Refs. 5 and 24; also see, for example, Refs.
10, 12, 17, 23, 25, and 27).
For the most part, physiological experiments have
proceeded with little information about the afferent
receptor morphology or location. In lieu of structural
information, the experiments have employed a set of
assumptions that, as the observations reviewed below
indicate, are false. One of these propositions is a widely
believed assumption that the vagus supplies the GI
tract with simple, undifferentiated free nerve endings.
Furthermore, much of the classic work on vago-vagal
reflexes assumed, either implicitly or by default, that it
is practical to understand vagal afferent transduction
without knowing the morphology of the endings, the
structure of their accessory tissues, the receptive fields
of the endings, and, finally, the densities or the regional distributions of the endings.
In contrast, in the present survey, we approach vagovagal reflexes from the perspective of the receptor
morphology, and we take issue with these two conventional assumptions. The “simple ending” idea is
sharply contradicted by present evidence. The “transduction can be understood without knowing the receptor” idea is highly problematic. To put the issue in
perspective, it is hard to conceive of the dramatic
progress in the visual system having occurred only
from the stimulus side and if rods and cones were not
well characterized, if the pigmented epithelium were
not described, if ganglion cell receptive fields were not
understood, or if receptor distributions in the fovea and
the peripheral retina were not appreciated. Similar
arguments are equally compelling for the successes in
auditory, olfactory, and gustatory physiology.
As noted in an earlier review in this journal (8), the
lining of the GI tract is the largest vulnerable body
surface exposed to the external environment, and sensory mechanisms of this system participate in coordinating absorption of food, motility, secretion, tissue
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high-threshold afferents are also not covered in the
present review.
VAGAL MECHANORECEPTORS
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Structure and distribution of the receptors. Three
types of mechanoreceptors have been inferred from
functional and morphological observations, and two of
these types of vagal afferent endings terminate within
the smooth muscle wall of the gut. Of all of the vagal
afferent endings in the GI tract, the two mechanoreceptors in the smooth muscle are the ones about which
we have the most structural information. The first of
the endings to be characterized structurally is the
intraganglionic laminar ending (IGLE; Refs. 15 and
26). An IGLE consists of a plate of terminal puncta that
lies parallel to muscle layers and that is situated at the
surface of myenteric ganglion, effectively at the boundary between a ganglion and one of the smooth muscle
layers (see Fig. 1). The IGLE appears to be anchored to
both the ganglion and the over- or underlying muscle
layer by glial processes (14), and it has been hypothesized that this biophysical arrangement allows the
IGLE to transduce shearing forces produced in association with changes of tension (both active and passive)
and stretch in the muscle wall. If these terminal plates
formed at the distal tips of the vagal afferents utilize
accessory tissues as part of the receptor unit, then
presumably the accessory elements must be either the
glial cells that tie the plates of puncta to the ganglion
and adjacent muscle sheet or the cells of the myenteric
ganglia.
An individual vagal afferent fiber that forms an
IGLE will typically ramify into several short terminal
telodendria, each of which ends in an individual IGLE.
These terminal branches issue separate IGLEs onto
several neighboring myenteric ganglia or poles of these
ganglia. Presumably, the receptive field of such an
afferent corresponds to the area of the muscle wall that
all of the clusters of IGLE plates on its telodendria
contact (cf. Ref. 35). In some cases, individual fibers
give off collaterals that travel considerable distances
after diverging to terminate in separate assemblages of
IGLEs, perhaps providing the multiple distinct receptive fields reported for some fibers (2). Although the
number of vagal afferent fibers supplied to the GI tract
might seem relatively modest, in light of the extensive
areas covered by the system of IGLE plates at the end
of an individual fiber, the vagus appears to supply an
extensive network of overlapping receptive fields in the
wall of the gut. Vagal afferents supply IGLEs to essentially the entire length of the GI tract, but they are
concentrated most densely in the rostral GI tract and
become progressively less dense along the length of the
GI tract (e.g., Refs. 3 and 31).
The second type of vagal afferent found in GI smooth
muscle differs dramatically from the IGLE in both
location and morphology. This ending has only recently
been described (4) and still more recently named the
intramuscular array (IMA; cf. Ref. 31). An IMA consists of a series of long terminal telodendria located
within either the circular or longitudinal muscle sheets
and that run parallel to smooth muscle fibers of the
sheet and to each other. These arrays of telodendria
are interconnected by short branches or cross bridges
(Fig. 2). The separate terminal telodendria forming one
of the arrays lie on a scaffolding formed by the interstitial cells of Cajal, which also lie within the smooth
muscle sheets and which run parallel to muscle fibers
(4, 7). On the basis of both their morphology and their
distributions and concentrations within the muscle
wall, it has been hypothesized that these IMAs appear
to be specialized to transduce stretch of the organ wall
(20). If the IMAs have accessory cells complexed with
them to form receptor units, then the accessory tissue
is presumably the interstitial cell of Cajal network.
Mutant mice with disturbances of this network have
losses of vagal IMAs (7), suggesting that the interstitial scaffolding provides either trophic or structural
support for the IMAs. As it enters the muscle wall, an
individual vagal afferent often branches to terminate
in two or more separate IMAs in neighboring areas of
the smooth muscle (see Ref. 20). Presumably the receptive fields of such afferents correspond to the area
encompassed by the IMA or IMA complex at their
peripheral terminals.
The two classes of endings in smooth muscle differ as
strikingly in their regional distributions as in their
morphology, tissue targets, and accessory cells. With
the use of a neural tracer that comprehensively labels
afferent terminals in the gut (i.e., wheat germ agglutinin-horseradish peroxidase) and a whole mount sampling technique, the regional distributions of the different types of afferents can be inventoried (Fig. 3; see
also Refs. 19 and 31). IGLEs are widely distributed
throughout the gut and occur in highest densities in
the antrum and corpus of the stomach and the initial
segment of the duodenum; their densities are reduced
in the forestomach, in the region of GI sphincters, and
in the distal small and large intestines. IMAs have
much more limited distributions, with concentrations
in the forestomach (in both longitudinal and circular
muscle layers) and in sphincters (in the circular muscle
of the sphincters). IMAs are rare in the intestines and
appear to occur almost exclusively at strategic sites
such as flexures and perhaps functional valves.
The third type of vagal mechanoreceptor has been
identified electrophysiologically and is postulated to be
mucosal, but the morphology of this type of ending has
not been clearly determined. Unlike the smooth muscle
endings, which appear to be slowly adapting, the mucosal receptors seem to be fast adapting.
Stimuli transduced by mechanoreceptors. A consideration of the disparate geometries of the IGLE and the
IMA illustrates the thesis that structural knowledge of
the receptor is needed. As we have reviewed elsewhere
(20), the architectures of the two endings as well as
their accessory tissues and their regional distributions
suggest that they must transduce different mechanical
forces (or, if they transduce the same forces, then they
must translate these forces into dissimilar neural
codes). We have proposed that their structural features
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Fig. 1. A vagal afferent fiber terminating in several intraganglionic laminar endings (IGLEs). The fiber was
labeled by injecting the anterograde neural tracer dextran-biotin into the nodose ganglion and then by processing
the stomach wall whole mount with a nickel-enhanced diaminobenzidine protocol. Neurons of the myenteric
ganglia were counterstained with cuprolinic blue. The specimen is from the gastric corpus, greater curvature
region, of a mouse. IGLEs consist of plates of terminal puncta apposed to myenteric neurons; these plates are
located at the interface between the myenteric ganglia and the smooth muscle layers they lie between. Tracing of
the axon forming IGLEs associated with several myenteric ganglia was made with the Neurolucida (Microbrightfield, Williston, VT) reconstruction system. A–F: photomicrographs, taken at the tracing sites denoted, illustrating
some of the individual IGLEs formed by the fiber. Presumably, the receptive field of this mechanoreceptor would
correspond to the area defined by the entire complex of separate IGLEs. For additional examples of individual
IGLEs, see Ref. 20. Scale bars ⫽ 50 ␮m.
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Fig. 2. A single intramuscular array (IMA). An individual branch
of a vagal afferent fiber (entering at the extreme top middle of
figure) terminates in this IMA. The fiber was labeled by injecting
the fluorescent anterograde tracer dextran into the nodose ganglion and then preparing the stomach wall as a whole mount for
fluorescence microscopy. The specimen is from the gastric forestomach, circular muscle sheet, of a rat. IMAs consist of complexes
of parallel telodendria distributed within smooth muscle. The
telodendria are associated with interstitial cells of Cajal (not
stained in this plate), and the IMA/interstitial cell units course in
parallel with smooth muscle fibers (just visible as the background
autofluorescence in this plate). A vagal afferent fiber may end in
several distinct IMAs distributed in the same region of one of the
muscle sheets. Presumably the receptive field of a fiber terminating in IMAs consists of the region encompassed by the complex of
separate IMAs. For another example of an individual IMA, see
Ref. 20; for examples of IMA/interstitial cell arrangements, see
Ref. 7. Scale bar ⫽ 100 ␮m.
are consistent with the IGLE transducing tension and
the IMA detecting stretch. In particular, IGLEs have
the distribution throughout the gut and the architecture to make them sensitive to detecting complex
rhythmic motor activity, whereas IMAs have the regional concentrations and the morphological features
to register sustained nonrhythmic adjustments in
length or stretch. Details of the morphologies of the two
endings also make it more practical to consider the
design of focal and selective stimuli that should probe
the transduction processes of these afferents. As we
have discussed, the mechanical stimuli that have been
traditionally used to stimulate vagal afferents are too
indiscriminate and too nonspecific, confounding tension and stretch, to yield precise characterization of
afferent processing.
Of the three species of vagal mechanoreceptors, only
the effective stimuli for the IGLEs have been determined with specificity. In a powerful paradigm that
minimizes some of the hurdles that have stalled analysis of vagal afferent transduction and that promises to
refine such analyses, Zagorodnyuk et al. (35) performed acute experiments recording from a vagal axon
near an isolated square of gut wall, in an in vitro
situation that facilitates mapping the unit’s receptive
field, subjecting it to specific mechanical forces (e.g.,
circumferential extension), and then filling its axon
with an anterograde tracer that will identify its receptor ending(s). With this preparation, the investigators
were able to work with identified IGLEs from the
guinea pig cardia (as well as esophageal wall; see Ref.
34) and provided characterization of their receptive
fields, adaptation profiles, thresholds, and additional
electrophysiological characteristics.
No comparable analyses characterizing the response
properties of identified IMAs have been performed. In
an attempt to assess retrospectively whether earlier
recording work done on vagal afferents that were not
identified as to terminal structure might suggest that a
particular pattern of electrophysiological responses
was correlated with the IMA on the basis of regional
pattern of responses or some other feature, we recently
reviewed the literature on GI mechanoreceptors that
had accumulated before the recent characterizations of
the receptor architecture (20). For the most part, earlier electrophysiological analyses proved to have sample sizes that were too small and/or to lack enough
stimulus control and other information to make any
assignments, but the review did underscore several of
the controls required and a number of the issues that
need to be addressed with additional work. In addition,
the survey did suggest that, as outlined above, the
available information is consistent with the IGLEs
serving as tension receptors and the IMAs comprising
length or stretch detectors.
In stressing how little is known about transduction,
we do not mean to imply that nothing is known about
the sensitivity of vagal afferents innervating the gut.
Considerable strides have been made in the last decade
in identifying hormones, neuromodulators, and other
agents that modify ongoing and elicited activity in
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VAGAL CHEMORECEPTORS
Fig. 3. Regional concentrations of IGLEs and IMAs in gastric smooth
muscle. To label all vagal afferents, wheat germ agglutinin-horseradish
peroxidase was injected into the nodose ganglion. Gastric whole mounts
are then prepared with a protocol designed to standardize specimens
and processed with tetramethylbenzidine. Through the use of fiducial
points, an adjustable sampling template is then fitted to the whole
mount specimen to correct for organ size and stretch, and a counting
grid is used to inventory endings at locations in the sampling template.
Average counts from a group of animals are represented as contour
maps (bottom of A and B) and topographic maps (top of each panel)
referenced to a silhouette contour of the gastric wall. Some of the data
from Ref. 31 have been combined, recalculated, and regraphed. A:
IGLEs are widely distributed throughout the stomach, with the highest
concentrations found in the corpus-antrum area. B: IMAs, for the most
part, are limited to the forestomach (and sphincters, which are not
included in this graph). IMAs in circular muscle are found primarily in
the two-thirds of the forestomach nearest the lesser curvature, whereas
IMAs in the longitudinal muscle are concentrated in the two-thirds of
the forestomach nearest the greater curvature. Near the middle region of
the wall of the forestomach, the overlap of the IMAs in the two different
muscle layers produces a conspicuous peak concentration of the endings.
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Structure and distribution of the receptors. Compared with the characterizations of the structure of
smooth muscle mechanoreceptors, even less is known
about the morphology of vagal chemoreceptors. Mucosal endings were described in the anatomic work of Hill
(9), although at the time vagal origin of the fibers was
not established. More recently, they have been identified as vagal by injecting anterograde tracers into the
nodose ganglion (1, 21). These vagal endings are putative chemoreceptors (or at least some of them are
putative chemoreceptors; others may be the mucosal
mechanoreceptors that have been defined electrophysiologically). Labeled vagal terminals are widely distributed in lamina propria and situated among the intestinal crypts. Vagal afferents also enter and ramify in
individual villi of the mucosa. In general, these vagal
afferents appear to divide into terminal processes
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afferents. In the case of vagal mechanoreceptors, for
example, CCK (e.g., Ref. 27) GABA (e.g., Ref. 17),
leptin (e.g., Ref. 32), purinergic compounds (18), and
opioid receptor agonists (e.g., Ref. 16), among other
neuroactive agents, tune their sensitivity. This work,
however, can only achieve a certain level of precision if
the classes of mechanoreceptors are not distinguished,
if direct effects on first-order afferents cannot be discriminated from indirect effects associated with actions
on smooth muscle or enteric neurons, and if agents
that effect transduction cannot be distinguished from
other compounds that affect posttransduction events in
the afferents. A fuller understanding of the receptor
apparatus and its cascade of transduction events is the
type of information that will make such discriminations practical and will make complete assessment of
the earlier observations feasible.
Intracellular basis of vagal mechanoreceptor. Although three types of mechanoreceptors have been
provisionally identified on the basis of their structures
and/or response patterns and the differing architectures of the two in smooth muscle have been described,
the analyses of these endings have not reached the
precision of being able to stipulate the biophysical
events that translate shearing, tension, stretch, or
displacement into electrical signals in the first-order
afferents. Parsimony would suggest that it may be
possible to extrapolate from other mechanoreceptor
systems, and considerable information is available for
some of these prototypes. From such extrapolations, it
would seem probable that stretch-activated channels
(which have been shown to exist in some nodose neurons; see Ref. 29) might participate in the transduction
of mechanical stimuli and that the specific morphology,
accessory tissue matrix, and distribution of the different afferents would tune the afferents to particular
forces. As an example of the utility of having the
receptors specified, it has been possible to begin such
analyses and to associate calcium-binding proteins
such as calretinin with IGLEs, particularly those in the
esophagus (e.g., Refs. 6 and 11).
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mary stimulus energy has been transduced (as suggested, for example, by the careful analyses of CCK;
see Ref. 25).
The other approach that has implications for the
sensitivities of vagal afferents complements the first by
demonstrating that first-order vagal afferents (typically assessed at the level of the perikarya in the nodose
ganglion or, in some cases, in cross-sections of the
entire vagus) contain binding sites for many of the
transmitters, neuromodulators, hormones, neurotrophic factors, and cytokines that have been shown to
modulate vagal afferent activity (e.g., Ref. 36). For the
most part, however, such experiments cannot yet link a
perikaryon that has been characterized electrophysiologically or by receptor immunochemistry with a particular ending morphology.
Until the morphological specializations, including
the structural associations with any accessory cells, of
the different vagal afferent receptors are described and
mapped, it will be difficult to distinguish those substances that play an obligatory role in the transduction
pathway from those chemicals that may modulate the
(posttransduction) sensitivity of the different afferents
or that modify the local (pretransduction) milieu so as
to alter either the subsequent sensitivity of vagal afferents or the probabilities of transduction events occurring.
PERSPECTIVES
In other, more thoroughly characterized sensory systems, analysis of the afferent traffic that initiates reflexes has been approached by identification of each of
the basic elements that participate in signal transduction. This strategy has involved the use of complementary functional and structural approaches that progressively specify both the stimulus and the receptor
apparatus. In no instance has afferent transduction
been adequately characterized without knowledge of
the receptor. Delineation of the stimulus helps focus
morphological analyses of the receptors, and, in turn,
structural characterization of the receptor helps clarify
the features of the stimulus that are transduced. With
more precise understanding of both the stimulus and
the receptor, it then becomes practical to elucidate
which channels and membrane-bound or intracellular
receptors are found in the endings and which intracellular signaling events are downstream of the transduction process. Recent developments in the analysis of GI
afferent mechanisms suggest that the same formula
will yield success in developing a full explanation of
vago-vagal reflexes.
At least three specific applications of fuller characterizations of the structural features of vagal receptors
initiating the vago-vagal reflexes can be envisioned.
First, understanding the architecture, distribution,
and accessory tissue of a particular type of receptor
should make it practical to design more selective stimuli that do not confound a variety of energy dimensions
(e.g., active and passive tension) and complicate analyses of stimulus transduction. Second, fuller character283 • DECEMBER 2002 •
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within the villi, to run in conjunction with the network
of fibroblasts or fibroblast-like cells with the villi, and
to end near, or even apposed to, the basal side of
epithelial cells. These endings are found in close proximity to enterochromaffin cells as well. The concept
that the fibroblast network serves as accessory tissue
and provides a structural and/or trophic support for the
vagal afferents in the mucosa, one akin to the interstitial cell of Cajal scaffolding associated with IMAs, is a
reasonable hypothesis. Vagal mucosal afferents also
have been observed to make putative contacts with
mast cells in jejunal villi (33).
Most of the information available is based on a spatially very limited sample and comes from the duodenum (cf. Refs. 1, 21, and 31), although vagal afferents
innervate the jejunal mucosa (33) and occur as far
distal as the crypts of the colon (31). Whether these
mucosal endings have specializations in terms of their
densities, their locations, and their finer architectures
that distinguish them into subclasses responsible for
different submodalities is unclear. In general, structural analyses have not yet begun to assess the divergence of individual fibers, to differentiate types or
subclasses (presumably modalities), or to map the distributions of such endings. Whereas single mechanoreceptor fibers have been found to end in a multiplicity of
IGLEs or IMAs, it is unclear how extensive individual
vagal afferents to the mucosa may be. To classify and
analyze individual fibers, it will be necessary to use
protocols that label a few individual fibers in their
entirety, without staining so many neurites or other
elements that it is impractical to distinguish the components of a single ending (e.g., the protocols used to
label the single processes in Figs. 1 and 2). Conversely,
to quantify the topographic distributions of such endings, protocols that label all fibers are needed (for
example the wheat germ agglutinin-horseradish peroxidase protocol used for the inventories in Fig. 3 and
illustrated in other papers, e.g., Refs. 19 and 31).
Stimuli transduced by vagal chemoreceptors. Although studies have not yet examined transduction
mechanisms of any class of morphologically identified
mucosal ending, a variety of electrophysiological experiments have been performed (e.g., Ref. 13) and many
physiological experiments have made progress in identifying stimuli affecting vagal afferent activity (e.g.,
Refs. 10 and 25) or engaging vagal reflexes (e.g., Refs.
5 and 24). Two complementary approaches have converged on the issue of the sensitivities of first-order
vagal afferents, but they have not in a strict sense dealt
with transduction by identified vagal receptors.
One of the approaches involves demonstrating that
vagal mucosal afferents (typically monitored by recording from nodose ganglion perikarya or from teased
vagal fibers), much like vagal smooth muscle mechanoreceptors, are sensitive to several neurotransmitters,
neuromodulators, hormones, cytokines, and other endogenous neuroactive signals (e.g., Ref. 10). Although
some of these signals could be involved specifically in
the transduction cascade, most of these signals probably operate on vagal afferent sensitivity once the pri-
G1224
VAGO-VAGAL REFLEXES
We acknowledge the expert help of Dr. F. B. Wang (topographic
mapping of mechanoreceptors; Fig. 3) and Elizabeth J. Kieffer (Neurolucida analysis; Fig. 1).
We were supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-27627 and DK-61317.
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the different submodalities of afferents, not just more
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