David Grundy

Fundamentals of Neurogastroenterology: Basic Science

This review examines the fundamentals of neurogastroenterology that may underlie the pathophysiology of functional GI disorders (FGIDs). It was prepared by an invited committee of international experts and represents an abbreviated version of their consensus document that will be published in its entirety in the forthcoming book and online version entitled ROME IV. It emphasizes recent advances in our understanding of the enteric nervous system, sensory physiology underlying pain, and stress signaling pathways. There is also a focus on neuroimmmune signaling and intestinal barrier function, given the recent evidence implicating the microbiome, diet, and mucosal immune activation in FGIDs. Together, these advances provide a host of exciting new targets to identify and treat FGIDs and new areas for future research into their pathophysiology.

Distribution of the vanilloid receptor (VR1) in the gastrointestinal tract

The gastrointestinal (GI) tract responds to a variety of stimuli through local and centrally mediated pathways. Changes in the intestinal microenvironment are sensed by vagal, spinal, and intrinsic primary afferent fibers. Sensory nerve endings located close to the lumen of the GI tract respond to pH, chemical composition of lumenal contents, or distortion of the mucosa. Afferents within the muscle layers are thought to be tension sensitive, whereas those located within the myenteric plexus are also thought to respond to changes in chemical composition and humoral substances. Subpopulations of these afferent fibers are activated by capsaicin. However, the exact location of these nerves is currently not known. The vanilloid receptor (VR1) is a nonselective cation channel that is activated by capsaicin, acid, and temperature. Antibodies to VR1 make it possible to determine the location of these afferents, their morphology, and their relationships with enteric nerves and other cell types in the GI tract. VR1‐like immunoreactivity was observed on nerves within myenteric ganglia and interganglionic fiber tracts throughout the GI tract. VR1 nerves were also observed within the muscle layers and had an irregular profile, with varicose‐like swellings along their lengths. Blood vessels within the GI wall had VR1‐immunoreactive nerve fibers associated with them. VR1‐like nerves and other immunopositive cells were also observed within the mucosa. In summary, VR1‐like immunoreactivity was found in several locations within the GI tract and may provide sensory integration of chemical, physical, or inflammatory stimuli. VR1‐like fibers appear to be predominantly spinal in origin, but a few vagal VR1‐like fibers exist in the stomach. J. Comp. Neurol. 465:121–135, 2003.

Effects of cholecystokinin (CCK-8) on two classes of gastroduodenal vagal afferent fibre

In order to investigate the vagal afferent pathway responsible for the previously reported effects of cholecystokinin (CCK) on gastric emptying and food intake, single afferent fibres were recorded from the cervical vagus of urethane-anaesthetized ferrets. Sixty tension receptor afferents with receptive fields in the corpus, antrum, duodenum, jejunum and ileum all showed a resting level of discharge which was augmented powerfully by distension of the segment containing the ending. Close intraarterial injection of CCK-8 (100-200 pmol) caused relaxation in proximal regions, but enhanced contractile activity in more distal regions. Mechanoreceptor discharge closely followed intraluminal pressure at all times, indicating a sensitivity primarily to tension and no direct sensitivity to CCK. Only duodenal tension receptors were significantly excited by CCK (due to increased contractile activity), whereas those in the stomach showed a net decrease. Thirty-seven mucosal receptors from the corpus, antrum, duodenum and jejunum showed responses to luminal stimuli: predominantly light stroking, acidity and hypertonicity as has been previously described. No responses to glucose or amino-acid infusions could be evoked. However, mucosal fibres showed a strong sensitivity to close-intraarterially injected CCK-8 (3-200 pmol) in 19/26 fibres tested. These responses were unaffected by cholinergic blockade when tested. The data strongly suggest that in the ferret only vagal mucosal receptors are directly sensitive to CCK-8. These fibres are therefore likely candidates for mediating some of the reflex and behavioural effects of CCK when it is released from the gastrointestinal tract and acts directly on vagal sensory endings.

Sensory transmission in the gastrointestinal tract

Abstract  The gastrointestinal (GI) tract must balance ostensibly opposite functions. On the one hand, it must undertake the process of digestion and absorption of nutrients. At the same time, the GI tract must protect itself from potential harmful antigenic and pathogenic material. Central to these processes is the ability to ‘sense’ the mechanical and chemical environment in the gut wall and lumen in order to orchestrate the appropriate response that facilitates nutrient assimilation or the rapid expulsion through diarrhoea and/or vomiting. In this respect, the GI tract is richly endowed with sensory elements that monitor the gut environment. Enteric neurones provide one source of such sensory innervation and are responsible for the ability of the decentralized gut to perform complex reflex functions. Extrinsic afferents not only contribute to this reflex control, but also contribute to homeostatic mechanisms and can give rise to sensations, under certain circumstances. The enteric and extrinsic sensory mechanisms share a number of common features but also some remarkably different properties. The purpose of this review is to summarize current views on sensory processing within both the enteric and extrinsic innervation and to specifically address the pharmacology of nociceptive extrinsic sensory pathways.

Neuroanatomy of visceral nociception: vagal and splanchnic afferent.

Afferent fibres convey sensory information from the upper gastrointestinal tract to the central nervous system but the nature of this information is different for vagal and spinal pathways. Vagal afferents convey predominantly physiological information while spinal afferents are able to encode noxious events. Because of the different response profiles following activation of these pathways, it is likely that vagal and splanchnic afferents play different roles in mediating sensation.

Neuroanatomy of extrinsic afferents supplying the gastrointestinal tract

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.

Enteric nervous system

Purpose of review Our aim was to provide a synopsis of how the field of enteric neurobiology has advanced during the past year. Recent findings With such a large number of studies to choose from and given our emphasis in last years issue on developmental aspects of the enteric nervous system, we have focused on several key themes reflecting the current interest in the way the enteric nervous system is altered in disease. Summary The new basic science information gathered during the past year provides insight into pathophysiological processes and will pave the way for improved understanding of both organic and ‘functional’ gastrointestinal disorders.

Jejunal afferent nerve sensitivity in wild-type and TRPV1 knockout mice

The aim of this study was to investigate the contribution of the TRPV1 receptor to jejunal afferent sensitivity in the murine intestine. Multiunit activity was recorded in vitro from mesenteric afferents supplying segments of mouse jejunum taken from wild‐type (WT) and TRPV1 knockout (TRPV1−/−) animals. In WT preparations, ramp distension of the gut (up to 60 mmHg) produced biphasic changes in afferent activity so the pressure–response curve had an initial rapid increase in afferent discharge followed by a second phase of slower increase in activity. Afferent response to distension was significantly lower in TRPV1−/− than in WT mice. Single‐unit analysis revealed three functional types of afferent fibres: (1) low‐threshold fibres (2) wide dynamic range fibres and (3) high‐threshold fibres. There was a marked downward shift of the pressure–response curve for wide dynamic range fibres in the TRPV1−/− mice as compared to the WT controls. The afferent response to intraluminal hydrochloric acid (20 mm) was also attenuated in the TRPV1−/− mice. In contrast, the response to bath application of bradykinin (1 μm, 3 ml) was not significantly different between the two groups. The TRPV1 antagonist capsazepine (10 μm) significantly attenuated the nerve responses to distension, intraluminal acid and bradykinin, as well as the spontaneous discharge in WT mice. The WT jejunal afferents responded to capsaicin with rapid increases in afferent activity, whereas TRPV1−/− afferents were not at all sensitive to capsaicin. Previous evidence indicates that TRPV1 is not mechanosensitive, so the results of the present study suggest that activation of TRPV1 may sensitize small intestinal afferent neurones.

Sensory and Motor Responses to Rectal Distention Vary According to Rate and Pattern of Balloon Inflation

Anorectal motor activity and rectal sensation were recorded in 12 normal male subjects during ramp distention of the rectum with water and air at randomized rates of 10, 20, 50, and 100 mL/min and during intermittent rapid distention with air. There were no significant differences between the results of ramp inflation with water or with air, and the repeated infusion of the same medium yielded reproducible results. Ramp distention induced sigmoid pressure-volume profiles. Different sensations occurred at specific points on the pressure-volume curve and were maintained until succeeded by the next sensation. Initial perception of the distention occurred during the initial steep pressure increase, the sensation of wind occurred during the plateau phase, and the desire to defecate occurred at the onset of the final rapid ascent. Rectal sensations were induced at lower volumes at low infusion rates when the slope of the pressure-volume relationship was shallower than at high infusion rates. This suggests that the receptor triggering rectal sensation is not a simple volume or pressure receptor, but is more likely to be a slowly adapting mechanoreceptor lying parallel to the circular muscle of the rectal wall. During rapid intermittent distention, the rectal volumes required to elicit rectal sensations were lower than during ramp distention, although the pressure-volume curve was steeper. Moreover, sensations often only lasted a short period of time but recurred on deflation. These data suggest activation of an additional population of rapidly adapting or high threshold mechanoreceptors. Anal relaxation was always evoked by intermittent rectal distention and was almost always associated with a rectal sensation and an increase in external anal sphincter activity. In contrast, anal relaxation could be absent or delayed during ramp inflation, especially at lower infusion rates, suggesting that internal sphincter can maintain continence for a long period of time while the rectum is slowly filling. Rectal sensation and concomitant external anal sphincter activity was not associated with anal relaxation during ramp inflation; most subjects felt the sensation long after the pressure reached its lowest level. However, under all circumstances the onset of rectal sensation was associated with an increase of external anal sphincter electrical activity. In conclusion, the rectal sensory and anorectal motor responses to distention depend on the rate and pattern of distention, which may activate a different population of receptors. Results from different laboratories cannot be compared directly unless the pattern and rate of distension are the same.

Vagal afferent discharge from mechanoreceptors in different regions of the ferret stomach.

1. The rate and volume of gastric filling was estimated in conscious ferrets by measuring the amount of milk they would drink after an overnight fast. The mean volume was 94.5 +/‐ 7.5 ml. at a rate of 13.0 +/‐ 0.74 ml./min. An intragastric infusion rate of 10 ml./min to a total of 50 ml. was selected as a standard distension stimulus. 2. Action potentials were recorded from single gastric afferent fibres in the cervical vagus. All but two of thirty‐six afferent units were tonically active when the stomach was deflated. 3. Afferent fibres arising from receptors in the antrum showed modulation in phase with spontaneously occurring antral contractions. Afferent fibres from the corpus and fundus, however, discharged at irregular rates between 0.35 and 7.5 Hz with no correlation with the intragastric pressure rises associated with the antral contractions. 4. Inflation of the stomach with 50 ml. 0.9% NaCl at a rate of 10 ml./min stimulated antral motility and the rhythmic afferent discharge from the antrum was enhanced Receptors in the corpus and fundus increased their rate of discharge with increasing gastric volumes. Receptors in the region between the antrum and the corpus had the property of both types so that they responded to both distension and contractions. 5. On distension with 0.9% NaCl, fluid is distributed unevenly in the stomach. 80% was accommodated in the corpus and fundus, the remainder of the fluid entering the antrum. 6. The tension was measured in strips of stomach wall taken from corpus and antrum. For equal increments of stretch the development of tension was greater in the antral than in corpus strips. This physical property together with neurally mediated receptive relaxation of the corpus is the reason for the fluid distribution described above. 7. It is concluded that the properties of the tension receptor are determined by their site in the stomach. Those in the body and fundus signal the degree of distension and those in the antrum signal information concerning the amplitude, rate and duration of antral contractions.