158 Efficacy of ATI-7505, a Novel Highly Selective 5-HT 4 Receptor Agonist, in a Rodent Model of Colonic Hypersensitivity.

Abstract

Background: Irritable bowel syndrome (IBS) is a common functional bowel disorder characterized by abdominal pain and abnormal gastrointestinal (GI) motility of uncertain etiology. While serotonergic agents have proven efficacious in IBS and other motility disorders, side effects have caused some of those compounds to be restricted from general use, causing a need for the development of more selective therapeutics. ATI-7505 is a new 5-HT4 receptor agonist which in clinical trials has been shown to improve upper and lower GI dysmotility. However, the effect of ATI-7505 on visceral pain has not been determined. The purpose of this study was to determine the efficacy of ATI-7505 in a rodent model of colonic hypersensitivity. Methods: Experiments were performed on ageand weight-matched male rats (n=8 per group) that were acclimated to the laboratory and experimenter. Colonic hypersensitivity was induced by an intracolonic administration of 0.6% acetic acid, which is known to sensitize luminal afferents in the absence of tissue damage or inflammation. The acetic acid was delivered 1 hour before determination of the sensitivity to colorectal balloon distension (CRD). Colonic sensitivity was measured by determining a visceromotor response (VMR) to CRD as assessed by the number of abdominal contractions in response to graded isobaric tonic distensions (15-60 mmHg, 10 min). All data were normalized as % of the response measured at 60 mmHg in a non-sensitized naive group. ATI-7505 (0.01-10 mg/kg) or vehicle was given via oral gavage 30 min before CRD. Results: In vehicle-treated rats, colonic hypersensitivity to CRD was apparent at all distension pressures. ATI-7505 dose-dependently reduced the exaggerated VMR response to CRD to the level of the naive control group (Table 1). Summary and Conclusions: ATI-7505 significantly inhibited hypersensitivity in a rodent model of acute colonic hypersensitivity. ATI-7505 may be a useful therapeutic for not only motility but also functional disorders involving visceral pain, such as IBS. Table 1: Effect of ATI-7505 on colonic sensitivity.