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.

• Authors: B J Wiskur, K Tyler, K Campbell-Dittmeyer, S R Chaplan, A D Wickenden, B Greenwood-Van Meerveld
• Journal: Methods and findings in experimental and clinical pharmacology (Methods Find Exp Clin Pharmacol) Vol. 32 Issue 8 Pg. 557-64 (Oct 2010) ISSN: 0379-0355 [Print] Spain
• PMID: 21132125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Chemical References

• 4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide
• Aminopyridines
• Piperazines
• TRPV Cation Channels
• TRPV1 receptor
• Trinitrobenzenesulfonic Acid
• Acetic Acid

Topics

• Acetic Acid
• Administration, Oral
• Aminopyridines (administration & dosage, pharmacology)
• Animals
• Colon (drug effects, physiopathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Irritable Bowel Syndrome (drug therapy, physiopathology)
• Male
• Piperazines (administration & dosage, pharmacology)
• Rats
• Rats, Wistar
• TRPV Cation Channels (antagonists & inhibitors)
• Trinitrobenzenesulfonic Acid