Chronic alcohol consumption induces a marked increase in NO synthesis by jejunal myenteric neurons, accompanied by an up-regulation of iNOS-expressing neurons and a downregulation of nNOS neurons. We conclude that the overproduction of NO may be a direct cause of gastrointestinal motility disturbances.

We recently described the widespread expression of somatostatin (SOM) receptors (SSTRs) in the non-inflamed and inflamed murine ileum. Surprisingly, no significant changes were observed in the SSTR2 expression during intestinal inflammation. These data, combined with several recent independent lines of investigation, raised some question about the long presumed central role of SSTR2 in the SOM-mediated effects in the physiological and pathological activity of the gastrointestinal (GI) tract. To further unravel the role of SSTR2 in GI physiology, we studied the expression of SOM and SSTRs in the normal and inflamed SSTR2 knockout/lacZ knockin (SSTR2(-/-)) ileum. The SSTR2(-/-) ileum was characterized by a widespread distribution of multiple SSTR subtypes in non-inflamed and inflamed conditions. Moreover, the absence of SSTR2 did not induce any compensatory effect in the distribution pattern or expression level of any of the other SSTR subtypes. In contrast, the amount of SOM mRNA was significantly lower in SSTR2(-/-) ileum than that in wild type animals. Quantitative analysis revealed a decreased number of SOM-expressing neurons in both enteric plexuses of the knockout animals, implying a possible link between the number of SOM-expressing enteric neurons and the expression of SSTR2 in the enteric nervous system. In conclusion, these data show that a reconsideration of the role of SSTR2 in the GI somatostatinergic effects is in order and further corroborate recent data on the role of other SSTR subtypes in the inflammatory effects of SOM during intestinal inflammation.

The recently suggested pivotal role of somatostatin (SOM) receptor 4 (SSTR4) in inflammation and nociception in several non-intestinal organs and in gastrointestinal (GI) physiology, necessitates exploration of the role of SSTR4 in GI pathophysiology. Therefore, the role of SSTR4 in GI activity was explored by investigating the effects of SSTR4 deficiency on intestinal motility, smooth muscle contractility and on the expression of SSTRs and neuropeptides in the healthy and Schistosoma mansoni-infected murine small intestine. Functional experiments revealed no differences in intestinal motility or smooth muscle cell contractility between wild-type and SSTR4 knockout (SSTR4–/–) mice in physiological conditions. As revealed by multiple immunofluorescent labellings, RT-PCR and quantitative real time RT-PCR (qPCR), genetic deficiency of SSTR4 considerably altered the expression of SOM and SSTRs in non-inflamed and inflamed conditions, affecting both extrinsic and intrinsic components of the intestinal innervation, along with SSTR expression in several non-neuronal cell types. Moreover, substance P and calcitonin gene-related peptide expression were significantly elevated in SSTR4–/– mice, confirming the modulatory role of SSTR4 on intestinal pro-inflammatory neuropeptide expression. These data suggest that SSTR4 plays a previously unexpected modulatory role in the regulation of intestinal SSTR expression. Moreover, in addition to the recently described inhibitory effects of SSTR4 on the neuronal release of pro-inflammatory peptides, SSTR4 appears also to be involved in the neuronal expression of both pro- and anti-inflammatory peptides in the murine small intestine.