A novel TRPV1 receptor antagonist JNJ-17203212 attenuates colonic hypersensitivity in rats.
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.
University of Oklahoma Health Sciences Center, Oklahoma Center for Neuroscience, Oklahoma City, Oklahoma, USA. brandt-wiskur@ouhsc.edu
B J
BJ
Wiskur
K
K
Tyler
K
K
Campbell-Dittmeyer
S R
SR
Chaplan
A D
AD
Wickenden
B
B
Greenwood-Van Meerveld
D019342:Acetic Acid; D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D043183:Irritable Bowel Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014302:Trinitrobenzenesulfonic Acid
C500065:4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide; D000631:Aminopyridines; D010879:Piperazines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014302:Trinitrobenzenesulfonic Acid; D019342:Acetic Acid