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Somatostatin is an inhibitory peptide present in abundance in the gastrointestinal (GI) tract. The effects of somatostatin are mediated through its interaction with a family of G-protein-coupled receptors, namely sst1-5. Previous evidence suggested that the sst2 receptor mediates an inhibitory role of somatostatin on GI afferent nerve sensitivity. In the present study we further evaluated mechanical and chemical sensitivity of mesenteric afferents in mice deficient in the sst2 receptor. Multi-unit recordings were made from mesenteric afferents from mouse jejunal segments perfused in vitro. Ramp distension of the jejunum up to 60 mmHg induced biphasic increases in afferent activity in both wild-type (WT) and sst2 gene knock-out (KO) mice. However, the level of afferent activity was significantly higher in the KO (n=15) compared to the WT (n=16) mice across the entire pressure range. The mesenteric afferent sensitivity to acid was evaluated by intraluminal infusion of hydrochloric acid (HCl 20 mM) for 2 min. Peak afferent discharge rate following acid infusion was significantly greater in KO (36.76 +/- 6.47 impulses s(-1), n=7) than in WT preparations (16.53 +/- 3.91 impulses s(-1), n=5, P<0.01). The response to bath-applied bradykinin (1 microm, 3 ml) was not significantly different in the KO and the WT preparations. It is interesting that in the WT preparations, octreotide inhibited both low- and high-threshold mechanosensory responses, whereas in the sst2 KO group it appeared to inhibit the low-threshold responses preferentially and failed to affect the high-threshold responses. The results of the present investigation demonstrate that sst2 deficiency is associated with exaggerated jejunal afferent sensitivity to both mechanical and chemical stimulations, suggesting that somatostatin plays an important inhibitory role in the control of visceral sensitivity by interacting with the sst2 receptor.

Ghrelin has been shown to decrease firing of gastric vagal afferents at doses comparable with circulating levels in the fasted state. This raises the possibility that ghrelin may have a hormonal action on other vagal afferent populations. The aim of this study was to determine the effects of ghrelin on jejunal afferent activity; including responses to distension, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) and cholecystokinin (CCK) in both naïve and vagotomized rats. Ghrelin significantly augmented the afferent response to distension. No effect was observed on baseline afferent discharge, or the response to 2-methyl-5-HT and CCK. The effect of ghrelin was more pronounced at lower ramp distending pressures (0-30 mmHg). Similarly, ghrelin augmented the jejunal afferent responses to phasic distension at 10-30 mmHg, but had no effect at higher pressures. Chronic subdiaphragmatic vagotomy and administration of the growth hormone secretagogue receptor (GHS-R) antagonist [D-Lys3]-GHRP-6 prevented the augmentation of the afferent responses to distension indicating ghrelin is acting through the GHS-R on vagal afferent fibres. Ghrelin augments the mechanosensation of jejunal vagal afferents and hence may lead to increased perception of hunger contractions.

A variety of inflammatory mediators and local metabolites, have been implicated in the sensitivity of intestinal afferent fibres to brief periods of ischaemia and reperfusion. As yet, the contribution of the vanilloid transient receptor potential (TRPV)1 receptor to the response to intestinal ischaemia remains undetermined. In the present study, the effect of pretreatment with the competitive TRPV1 antagonist capsazepine and the non-selective TRPV channel antagonist ruthenium red, on the mesenteric afferent fibre response to ischaemia was examined. In control animals there was a reproducible biphasic increase in whole nerve afferent fibre activity during two brief periods of ischaemia. Treatment with ruthenium red significantly attenuated the early phase increase in afferent fibre activity during ischaemia. However, capsazepine treatment did not significantly alter the afferent fibre response to either ischaemia or reperfusion. Further experiments in chronically vagotomized animals indicated that the early phase response to ischaemia was mediated via vagal afferent fibres. The mechanism via which ruthenium red selectively inhibited vagal afferent fibres during ischaemia is unknown, but it does not appear to involve blockade of the TRPV1 receptor.

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 microm, 3 ml) was not significantly different between the two groups. The TRPV1 antagonist capsazepine (10 microm) 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.