Activation of peripheral 5-HT receptors attenuates colonic sensitivity to intraluminal distension.

Abstract

Tegaserod is a 5-HT(4) receptor partial agonist approved for the treatment of irritable bowel syndrome in women with constipation and in both men and women with chronic constipation. The efficacy of tegaserod is based on the importance of 5-HT(4) receptors regulating intestinal peristalsis and secretion, and possibly visceral sensory pathways. Our aim was to investigate the effect of tegaserod on colorectal sensitivity using models of normal and exaggerated responsiveness to colorectal distension (CRD). The visceromotor responses (VMR) to CRD at graded pressures (0-60 mmHg) were measured by the number of reflex abdominal contractions. Acute colorectal hypersensitivity was induced by intracolonic infusion of dilute acetic acid. Chronic hypersensitivity was observed in rats following spontaneous resolution of trinitrobenzenesulfonic acid-induced colitis. Rats with normosensitive colons served as controls. Tegaserod (0.1-10 mg kg(-1)) caused dose-dependent reduction of the VMR to CRD in control rats and in those with colonic hypersensitivity. 5-HT(4) antagonists reversed the effects of tegaserod in rats with normosensitive colons, and partially inhibited effects in rats with colonic hypersensitivity. Central administration of tegaserod had no inhibitory effect. These results support the assumption that colonic hypersensitivity could be normalized by tegaserod acting, at least in part, through peripheral 5-HT(4) receptors.

• Authors: B Greenwood-Van Meerveld, K Venkova, G Hicks, E Dennis, M D Crowell
• Journal: Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society (Neurogastroenterol Motil) Vol. 18 Issue 1 Pg. 76-86 (Jan 2006) ISSN: 1350-1925 [Print] England
• PMID: 16371086 (Publication Type: Journal Article)

Chemical References

• (1-piperidinyl)ethyl 1H-indole-3-carboxylate
• Gastrointestinal Agents
• Indoles
• Piperidines
• Serotonin Receptor Agonists
• Receptors, Serotonin, 5-HT4
• tegaserod
• Trinitrobenzenesulfonic Acid
• Acetic Acid

Topics

• Acetic Acid
• Animals
• Colitis (chemically induced, pathology)
• Colon (drug effects, physiology)
• Dose-Response Relationship, Drug
• Gastrointestinal Agents (administration & dosage, pharmacology)
• Indoles (administration & dosage, pharmacology)
• Injections, Intraventricular
• Male
• Muscle, Smooth (drug effects)
• Piperidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Serotonin, 5-HT4 (drug effects)
• Rectum (physiology)
• Serotonin Receptor Agonists (administration & dosage, pharmacology)
• Trinitrobenzenesulfonic Acid