Title Page ATB-429, a hydrogen sulfide-releasing derivative of mesalamine, exerts anti-nociceptive effects in a model of post-inflammatory hypersensitivity

Hydrogen sulfide (H2S) functions as a neuromodulator and exerts anti-inflammatory activities. Recent data indicate that irritable bowel syndrome (IBS) is linked to inflammation of the gastrointestinal tract. In this study we have investigated the role of a novel H2Sreleasing derivative of mesalamine (ATB-429) in modulating nociception to colorectal distension (CRD), a model that mimics some features of IBS, in healthy and post-colitic rats. Four, graded (0.4-1.6 ml water) CRD were produced in conscious rats and colorectal sensitivity and pain were assessed by measuring the abdominal withdrawal response (AWR) and spinal c-Fos expression. In healthy rats, ATB-429 dose-dependently (25, 50 or 100 mg/kg) attenuated CRD-induced hypersensitivity and significantly inhibited CRDinduced overexpression of spinal cFOS mRNA, while mesalamine had no effect. ATB-429induced anti-nociception was reversed by glibenclamide, a KATP channel inhibitor. The antinociceptive effect of ATB-429 was maintained in a rodent model of post-inflammatory hypersensitivity (4 weeks after colitis induction). At a dose of 100 mg/kg, ATB-429 reversed the allodynic response caused by CRD in post-colitic rats. Colonic COX-2 and IL1β mRNA and spinal cFOS mRNA expression were significantly down-regulated by ATB429, but not by mesalamine. ATB-429, but not mesalamine, increased blood concentrations of H2S in both healthy and post-colitic rats. Taken together these data suggest that ATB-429 inhibits hypersensitivity induced by CRD in both healthy and postcolitic, allodynic rats by a KATP channel-mediated mechanism. This study provides evidence that H2S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on July 19, 2006 as DOI: 10.1124/jpet.106.106435 at A PE T Jornals on Sptem er 3, 2017 jpet.asjournals.org D ow nladed from