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J Physiol Volume 581, Number 2, 779-786, June 1, 2007 DOI: 10.1113/jphysiol.2006.125187
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ALIMENTARY

Spontaneous hypersensitivity in mesenteric afferent nerves of mice deficient in the sst2 subtype of somatostatin receptor

 Weifang Rong1,3, Wendy J. Winchester2 and David Grundy1

1 Department of Biomedical Science, University of Sheffield, Alfred Danny Building, Western Bank, Sheffield S10 2TN, UK
2 Neurology & GI Centre for Excellence for Drug Discovery, GlaxoSmithKline R & D Ltd, Harlow, Essex CM19 5AW, UK
3 Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China

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 µM, 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.

(Received 20 November 2006; accepted after revision 13 March 2007; first published online 15 March 2007)
Corresponding author D. Grundy: Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.   Email d.grundy{at}sheffield.ac.uk






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