Richard Anthony Borman

Serotonergic modulation and irritable bowel syndrome

Irritable bowel syndrome (IBS) is a debilitating disease, which is characterised by recurrent abdominal cramping and pain, and is associated with either constipation and/or diarrhoea. It is approximately twice as prevalent in women as it is in men and is among the most common gastrointestinal (GI) disorders encountered in primary care. The aetiology of the disease is poorly understood but may include motility dysregulation, visceral sensitivity, inflammation, bacterial infection, dietary antigens, psychological stress, GI surgery or a gut-brain phenomenon. At present, there is no acceptable treatment for IBS, although recent advances indicate that some relief may be achieved by the administration of compounds that act on 5-HT (serotonin) receptors. This suggestion is the result of numerous studies which have shown that 5-HT may exert a number of diverse effects on human GI tissues. In addition, it has emerged that the levels of the 5-HT metabolite (5-HIAA) are raised in the plasma of IBS patients and that administration of 5-HT-like compounds may mimic the symptoms of IBS. It has therefore been proposed that therapy with compounds that act at 5-HT receptors will return the intestine to normal activity and alleviate the pain experienced by these patients. One compound (alosetron, a 5-HT3 receptor antagonist) has already been released onto the market but showed benefit in female patients only and only in those whose primary symptom was diarrhoea. In addition, the compound was recently withdrawn following concerns over its safety. The reasons why alosetron only appears to show efficacy in females, why these treatments are only effective in a subset of the population of IBS patients and why alosetron elicits its particular side effect profile have not been elucidated. One further serotonergic compound, tegaserod (Zelmac™, a 5-HT4 receptor agonist), has shown promise for the treatment of patients with constipation-predominant IBS and is currently in pre-registration for this indication. It is clear, however, that further research will have to take place before the utility of serotonergic modulation in the treatment of IBS can be fully validated.

S1736 EP4 Receptor Blockade Inhibits Epithelial Ion Secretion Induced By PGE2, TNFα and Il1β in Human Colon

Introduction: Increased levels of proand anti-inflammatory cytokines were observed in various segments of histologically intact small intestines in animal models of acute and chronic colitis. We recently demonstrated that these cytokines are produced de novo shortly after the induction of colitis. The trigger for this upregulation is not known. Aim: To study the possible neural involvement in the synthesis of inflammatory cytokines in remote areas from the ulcer site in rat models of colitis. Methods: Colitis was induced by rectal instillation of trinitrobenzenesulphonic acid (TNBS) or iodoacetamide in adult Sprague-Dawley rats. The capsaicin sensitive primary afferents (CSPA) were ablated using subcutaneous injections of capsaicin at time 0 (25mg/kg), 8 and 32 hours (50mg/kg). Using real time PCR, TNF-α and IL-10 mRNA expression was measured in mucosal scrapings of the duodenum, jejunum, ileum and colon at different time intervals after induction of colitis. Results: TNF-α mRNA expression increased by 3-40 times in the different intestinal segments (p<0.05) 48h after iodoacetamide induced colitis. CSPA ablation completely inhibited this upregulation in the small intestine but not in the colon. Similar results were obtained in TNBS induced colitis. Intestinal IL-10 mRNA expression increased by 6-43 times (p<0.01) 48h after iodoacetamide administration. This increase was abolished in rats subjected to CSPA ablation except in the colon where IL-10 further increased by 2 times (p<0.05). In TNBS group, there was respectively a 4-12 and 4-7 folds increase of small intestinal IL-10 mRNA expression at 1 and 21 days after colitis induction (both p<0.01). This increase was not observed in rats pretreated with capsaicin. Both capsaicin treated and untreated rats elicited a similar visual ulcer score after colitis induction. Conclusion: Intestinal CSPA fibers play a key role in the induction of a de novo synthesis of inflammatory cytokines in intestinal segments distant from the site of colitis. The study was supported by the medical practice plan (MPP) and university research board (URB), American University of Beirut-Lebanon.