A novel TRPV1 receptor antagonist JNJ-17203212 attenuates colonic hypersensitivity in rats

Abstract

This study examined the efficacy of a novel TRPV1 antagonist, JNJ-17203212, in two experimental rat models that exhibit a hypersensitive visceral motor response (VMR) to colorectal distension (CRD). In the first model, intraluminal administration of acetic acid (1% solution) into the distal colon produced an acute colonic hypersensitivity. In the second model, intraluminal administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) into the distal colon produced a chronic, post-inflammatory colonic hypersensitivity 30 days post-TNBS administration. Throughout this study, colonic sensitivity was assessed via quantification of VMR to CRD in rats following a single, oral administration of JNJ-17203212 (3, 10 or 30 mg/kg) or vehicle. Intraluminal administration of acetic acid and TNBS resulted in increased VMR to CRD when compared to controls. In both groups, VMR to CRD was significantly reduced by administration of JNJ-17203212 at 30 mg/kg. The results of this study show that the selective TRPV1 antagonist, JNJ-17203212, reduces sensitivity to luminal distension in both an acute, noninflammatory and a chronic, post-inflammatory rodent model of colonic hypersensitivity. These data indicate that TRPV1 is involved in the pathogenesis of visceral hypersensitivity and that JNJ-17203212 may be a potential therapeutic agent for functional bowel disorders characterized by abdominal hypersensitivity, such as irritable bowel syndrome.