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Keywords:

  • intraganglionic laminar endings;
  • mechano sensitivity;
  • visceral hypersensitivity;
  • visceral afferent

Abstract

  1. Top of page
  2. Abstract
  3. Central destination and access pathways of extrinsic afferents
  4. Distribution of afferent terminals in the gut and structure–function relationship
  5. Terminal specializations
  6. Anatomical form vs mechanosensory function
  7. Functional plasticity and pathophysiological implications
  8. References

Here we discuss the neuroanatomy of extrinsic gastrointestinal (GI) afferent neurones, the relationship between structure and function and the role of afferents in disease. Three pathways connect the gut to the central nervous system: vagal afferents signal mainly from upper GI regions, pelvic afferents mainly from the colorectal region and splanchnic afferents from throughout. Vagal afferents mediate reflex regulation of gut function and behaviour, operating mainly at physiological levels. There are two major functional classes − tension receptors, responding to muscular contraction and distension, and mucosal receptors. The function of vagal endings correlates well with their anatomy: tracing studies show intramuscular arrays (IMAs) and intraganglionic laminar endings (IGLEs); IGLEs are now known to respond to tension. Functional mucosal receptors correlate with endings traced to the lamina propria. Pelvic afferents serve similar functions to vagal afferents, and additionally mediate both innocuous and noxious sensations. Splanchnic afferents comprise mucosal and stretch-sensitive afferents with low thresholds in addition to high-threshold serosal/mesenteric afferents suggesting diverse roles. IGLEs, probably of pelvic origin, have been identified recently in the rectum and respond similarly to gastric vagal IGLEs. Gastrointestinal afferents may be sensitized or inhibited by chemical mediators released from several cell types. Whether functional changes have anatomical correlates is not known, but it is likely that they underlie diseases involving visceral hypersensitivity.


Central destination and access pathways of extrinsic afferents

  1. Top of page
  2. Abstract
  3. Central destination and access pathways of extrinsic afferents
  4. Distribution of afferent terminals in the gut and structure–function relationship
  5. Terminal specializations
  6. Anatomical form vs mechanosensory function
  7. Functional plasticity and pathophysiological implications
  8. References

A rich afferent innervation conveys sensory information from the gastrointestinal tract to the central nervous system where gut reflex function is coordinated and integrated with behavioural responses (e.g. regulation of food intake). Afferent innervation also mediates sensations from the gut. These afferent fibres follow two routes to the central nervous system. Vagal afferents have their cell bodies in the nodose ganglia and project centrally to the nucleus tractus solitarius (NTS), while the cell bodies of spinal afferents are located in the dorsal root ganglia. Central projections of these afferent neurones enter the brain stem and spinal cord, respectively, and make synaptic connections with second order neurones that distribute visceral information throughout the central nervous system. Spinal afferents can be subdivided further into splanchnic and pelvic afferents. These largely follow the path of sympathetic and parasympathetic neurones that project to the gut wall and have preganglionic cell bodies in thoracolumbar and sacral spinal ganglia, respectively.

There are both anatomical and functional differences between different populations of sensory afferents supplying the GI tract. Vagal afferent endings are concentrated largely in the upper gastrointestinal tract, while pelvic afferents are limited to the lower bowel. In contrast the whole gastrointestinal tract probably receives an innervation by splanchnic afferents. The more focused distribution of vagal and pelvic afferents may correspond to the regions of the gut in which graded, innocuous sensations can be evoked by distension. In contrast, regions which receive only splanchnic afferent innervation appear to generate less graded sensation, with discomfort and frank pain the first responses to increasing levels of distension.

Ascending spinal pathways project ultimately to thalamic nuclei that relay information to higher centres. Second order neurones in the spinal cord respond to both visceral and somatic stimuli. This convergence onto spinothalamic, spinoreticular and the more recently described dorsal column pathways are responsible for the phenomenon of referred pain, whereby visceral sensation can be perceived as if originating from somatic sites (dermatomes).1,2 Projections of vagal afferent input from the nucleus tractus solitarius are mainly to hypothalamic and limbic structures associated with behavioural and emotional aspects of sensory processing.3

Terminal specializations

  1. Top of page
  2. Abstract
  3. Central destination and access pathways of extrinsic afferents
  4. Distribution of afferent terminals in the gut and structure–function relationship
  5. Terminal specializations
  6. Anatomical form vs mechanosensory function
  7. Functional plasticity and pathophysiological implications
  8. References

The peripheral terminals of vagal and spinal afferents can be localized within the gastrointestinal tract using neuronal tracing techniques. Studies using carbocyanine dyes such as DiI, wheatgerm agglutinin-conjugated horseradish peroxidase or dextran tracers have provided an extensive anatomical foundation for understanding the vagal afferent innervation of different layers and regions of gut.4,5 Recent studies have utilized the ability of neurobiotin to be taken up by nerve fibres in vitro and transported rapidly over (relatively) short distances to the nerve terminals within the gut wall.6 These more restricted dye-fills of fine branches of extrinsic nerve trunks to the gut wall7–9 have allowed correlation between structure and function to be investigated.

Functionally, three distinct and characteristic patterns of terminal distribution can be identified within the gut wall. One population of afferent fibres has responsive endings in the serosal layer and in the mesenteric connections often in association with mesenteric blood vessels. Another population has been traced into the muscularis externa and forms endings either in the muscle layers10–13 or in the myenteric plexus, which is sandwiched between the longitudinal and circular muscle layer.14 The third population makes endings in the mucosal lamina propria, where they are positioned to detect material absorbed across the mucosal epithelium or released from epithelial and subepithelial cells including enterochromaffin and immunocompetent cells15–18(Fig. 1).

image

Figure 1. Vagal afferent terminals in rat gastrointestinal tract anterogradely traced with the fluorescent dye DiI (bright white) injected into nodose ganglia. (A) Intramuscular array (IMA) in longitudinal muscle layer of gastric fundus. Arrow indicates parent axon entering the muscle layer from myenteric plexus. The inset shows vagal afferent fibres in intimate anatomical contact with interstitial cell of Cajal. (B) Intraganglionic laminar endings (IGLEs) in myenteric plexus of gastric fundus. Two different parent axons are indicated by arrows. Myenteric ganglion is indicated by arrowheads. (C) Mucosal endings close to epithelium (e) in villous of proximal duodenum.

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Anatomical form vs mechanosensory function

  1. Top of page
  2. Abstract
  3. Central destination and access pathways of extrinsic afferents
  4. Distribution of afferent terminals in the gut and structure–function relationship
  5. Terminal specializations
  6. Anatomical form vs mechanosensory function
  7. Functional plasticity and pathophysiological implications
  8. References

The three different populations of afferent endings have different sensory modalities responding to both mechanical and chemical stimulation generated within and outside the bowel wall.19–21 Nerve terminals in the serosa and mesentery are activated by distortion of the mesenteric attachments; this means that they do not signal distension or contraction of the bowel wall unless it is strong enough to evoke mesenteric or serosal distortion. Afferents within the muscle layers of the gut wall also respond to distension and contraction, but have lower thresholds for activation and reach maximal responses within physiological levels of distension. Vagal and pelvic muscular afferents show maintained responses to distension, whereas splanchnic muscular afferents may be more rapidly adapting.20,22–26 Mucosal afferents in all three pathways do not respond to distension or contraction but are exquisitely sensitive to mechanical deformation of the mucosa, such as might occur with particulate material within the lumen.20,27–29

Terminals in the longitudinal and circular muscle layers have been described as intramuscular arrays, consisting of several long (up to a few mm) and straight axons running parallel to the respective layer and connected by oblique or right-angled short connecting branches.10–13 These intramuscular arrays have been suggested to be in-series tension receptor endings, possibly responding to both passive stretch and active contraction of the muscle,5 although direct evidence for this is currently lacking. However, intramuscular arrays, together with interstitial cells of Cajal, are drastically and selectively reduced in the forestomach of mice with null mutations of the c-Kit receptor or the c-Kit receptor ligand steel factor, without a reduction in other types of vagal afferent endings.30,31 Meal pattern analysis in these mutant mice revealed decreased meal size and increased meal frequency, suggesting that the stomach is less able to accommodate large volumes.30 It is possible that this reflects impaired mechanosensitivity, due perhaps to the loss of IMAs. Vagal afferent terminals in the myenteric plexus throughout the gastrointestinal tract have been described as intraganglionic laminar endings (IGLEs).32,33 These endings are in intimate contact with the connective tissue capsule and enteric glial cells surrounding myenteric ganglia and have long been hypothesized to detect mechanical shearing forces between the orthogonal muscle layers.33

Evidence for such a mechanosensory function of IGLEs has been elaborated by mapping the receptive field of vagal afferent endings in the oesophagus and stomach and showing morphologically that individual ‘hot spots’ of mechanosensitivity correspond to single IGLEs.7,8 Similar structures have been described more recently in the colon and rectum.9 Recording from nerve bundles running between the pelvic ganglia and the colon and rectum has revealed low-threshold slowly adapting mechanoreceptors, similar to those in the oesophagus and stomach, which could be activated both by gut distension and by focal mechanical probing. Analysis of dye-filling revealed specialized endings in guinea-pig myenteric ganglia which correspond to the transduction sites of rectal mechanoreceptors. These endings have been called rectal IGLEs (rIGLEs, Fig. 2).9 Typically they appear as flattened leaf-like endings located in myenteric ganglia comparable to gastric IGLEs but generally smaller and simpler in structure. These endings arise probably from sacral dorsal root ganglia with a single axon usually giving rise to multiple rIGLEs, each one corresponding to a separate transduction site. This type of low-threshold slowly adapting mechanosensitivity was not encountered for splanchnic afferents to the colon, suggesting that IGLEs may be the transduction site specifically for the low threshold mechanoreceptors in both vagal and pelvic nerve fibres. The different stimulus response profiles of vagal, splanchnic and pelvic mechanoreceptors are compatible with the concept of vagal afferents being involved in physiological regulation, pelvic afferents being involved in both physiological regulation and pain, and splanchnic afferents (e.g. Fig. 3) mediating mainly pain.1,19,21 IGLEs may also respond to chemical stimuli such as acetylcholine and ATP raising the possibility that these endings also play a key in the sensory role in detecting release of mediators from within the synaptic neuropil of the myenteric ganglia or surrounding tissues.34 However, evidence that such chemosensory mechanisms contribute to mechano-transduction is lacking.

image

Figure 2. Biotinamide fill of a rectal IGLE (rIGLE) in a myenteric ganglion of the guinea-pig rectum. Note the fine flattened lamellar endings that distinguish this type of ending from varicose axons. Calibration bar: 50 µm (courtesy of Catharina Olsson).

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image

Figure 3. Recording from mesenteric afferents supplying the mouse jejunum. The top trace is a sequential rate histogram of whole nerve afferent discharge. The middle trace shows the raw nerve recording while below shows the intraluminal pressure rise during a ramp infusion of saline at a rate of 10 mL/ h (167 µL min−1). Note the biphasic increase in discharge. The first phase occurs with a minimal change in intraluminal pressure while the second phase represented by the large amplitude spike in the raw nerve trace occurs only at high distending pressures (courtesy of Weifang Rong). In the rat these first and second phases in the response have been shown to be mediated by different subpopulations of vagal and spinal afferents.39

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Mucosal terminals are most abundant in the proximal duodenum, becoming relatively sparse in the distal small intestine. In the rat duodenum and jejunum, vagal afferent fibres penetrate the circular muscle layer and submucosa to form networks of multiply branching axons within the lamina propria of both crypts and villi.15–18 Terminal axons are in close contact with, but do not seem to penetrate, the basal lamina and are thus in an ideal position to detect substances including absorbed nutrients and mediators released from both epithelial cells and other structures within the lamina propria. No attempt has been made to date to identify histologically vagal and spinal afferent fibre terminals in the mucosa of the large intestine. Functional evidence, however, shows vagal splanchnic and pelvic mucosal mechanoreceptors supplying all regions of the gastrointestinal tract. They are characterized by low thresholds to mechanical stimuli, such as stroking with a fine brush, relatively rapid adaptation to continuous stimulation and in most cases sensitivity to a variety of chemical stimuli (polymodal receptors).20,27–29,35–37 Serosal and mesenteric receptors also frequently show evidence of chemosensitivity. This may translate to a responsiveness to factors circulating or released locally, especially in view of their localization on or near blood vessels.20,22,36–38 Recent data show that there are distinct subpopulations of serosal and mesenteric afferents − one population is chemosensitive and one nonchemosensitive to chemical agents (such as ATP bradykinin, capsaicin, 5-HT and histamine).36,38

Functional plasticity and pathophysiological implications

  1. Top of page
  2. Abstract
  3. Central destination and access pathways of extrinsic afferents
  4. Distribution of afferent terminals in the gut and structure–function relationship
  5. Terminal specializations
  6. Anatomical form vs mechanosensory function
  7. Functional plasticity and pathophysiological implications
  8. References

In addition to evoking direct responses, a wide range of chemical mediators may influence mechanosensitivity, particularly that of spinal afferents. These mediators can be released in the conditions of inflammation, injury or ischaemia from a variety of cell types, for example: platelets, leucocytes, lymphocytes, macrophages, mast cells, glia, fibroblasts, blood vessels, muscles and neurones. Each of these specific cells (e.g. mast cells) may release several of these modulating agents, some of which may act directly on the sensory nerve terminal while others may act indirectly, causing release of other agents from other cells in a series of cascades. The net effect of this promiscuous chemosensitivity is that the properties of sensory neurones can change (often referred to as plasticity).34 Sensory neuronal plasticity may have a rapid onset and this is described as peripheral sensitization, because the changes take place at the level of the sensory nerve terminal following release of a great many algesic chemicals. Other endogenous chemical mediators can downregulate afferent sensitivity such that an imbalance in pro- and antisensitizing mechanisms may lead to a disordered sensory signal. One example is that of somatostatin acting via the SST2 receptor. Receptor antagonists of the SST2 receptor augment the response to bradykinin, suggesting that endogenous somatostatin is serving to hold back the sensitivity to this algesic chemical.39 Of clinical relevance to functional bowel disorders, such as irritable bowel syndrome, is the increased sensitivity to both to mechanical and chemical stimulation that may contribute to chronic pain states. Moreover, as these afferents also serve to trigger reflex mechanisms that control and coordinate gut function, their sensitization may also cause hyper- or dysreflexia.

References

  1. Top of page
  2. Abstract
  3. Central destination and access pathways of extrinsic afferents
  4. Distribution of afferent terminals in the gut and structure–function relationship
  5. Terminal specializations
  6. Anatomical form vs mechanosensory function
  7. Functional plasticity and pathophysiological implications
  8. References
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