H(2)S 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 H(2)S-releasing derivative of
mesalamine (5-amino-
2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]
dithiol-3yl)-phenyl
ester, ATB-429) in modulating nociception to colorectal distension (CRD), a model that mimics some features of IBS, in healthy and postcolitic rats. Four graded (0.4-1.6 ml of water) CRDs were produced in conscious rats, and colorectal sensitivity and
pain were assessed by measuring the abdominal withdrawal response 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 CRD-induced overexpression of spinal c-FOS
mRNA, whereas
mesalamine had no effect. ATB-429-induced antinociception was reversed by
glibenclamide, a
ATP-sensitive K(+) (K(
ATP)) channel inhibitor. The antinociceptive effect of
ATB-429 was maintained in a rodent model of postinflammatory
hypersensitivity (4 weeks after
colitis induction). At a dose of 100 mg/kg,
ATB-429 reversed the allodynic response caused by CRD in postcolitic rats. Colonic
cyclooxygenase-2 and interkeukin-1beta
mRNA and spinal c-FOS
mRNA expression were significantly down-regulated by
ATB-429, but not by
mesalamine.
ATB-429, but not
mesalamine, increased blood concentrations of H(2)S in both healthy and postcolitic rats. Taken together, these data suggest that
ATB-429 inhibits
hypersensitivity induced by CRD in both healthy and postcolitic, allodynic rats by a K(
ATP) channel-mediated mechanism. This study provides evidence that H(2)S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders.