cp-154526 and Colitis

Gastroenteritis is one of the risk factors for developing irritable bowel syndrome (IBS). However, the precise mechanism of postinfectious IBS is still unknown. We tested the hypothesis that a combination of previous inflammation and repetitive colorectal distention (CRD) makes the colon hypersensitive and that treatment with a corticotropin-releasing hormone receptor 1 (CRH-R1) antagonist blocks this colonic hypersensitivity. Rats were pretreated with vehicle or 2,4,6-trinitrobenzene sulphonic acid (TNBS) 6 weeks before CRD. For the CRD experiment, the colorectum was distended once a day for six consecutive days. The CRH-R1 antagonist (CP-154,526, 20 mg kg(-1)) or vehicle was injected subcutaneously 30 min before CRD. Visceral perception was quantified as visceromotor response (VMR) using an electromyograph. For histological examination, the rats were killed on the last day of CRD experiment, and haematoxylin and eosin-staining of colon segments was performed. Although from the first to the third day of CRD, VMRs increased in both the vehicle-treated rats and TNBS-treated rats, they were significantly higher in TNBS-treated rats than those in vehicle-treated controls. On the fifth day of CRD, however, VMRs in the vehicle-treated rats were significantly greater than those in TNBS-treated rats. Pretreatment of rats with CP-154,526 significantly attenuated the increase in VMR induced by repetitive CRD with previous inflammation. Finally, we found that repetitive CRD and repetitive CRD after colitis induced visceral inflammation. These results indicate that a combination of previous inflammation and repetitive CRD induces visceral hypersensitivity and that a CRH-R1 antagonist attenuates this response in rats.

Topics: Animals; Colitis; Colon; Dilatation, Pathologic; Electromyography; Humans; Inflammation; Irritable Bowel Syndrome; Male; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Trinitrobenzenesulfonic Acid