5-Amino-2-hydroxybenzoic Acid 4-(5-Thioxo-5H-[1,2]dithiol-3yl)-phenyl Ester(ATB-429),a Hydrogen Sulfide-Releasing Derivative of Mesalamine,Exerts Antinociceptive Effects in a Model of Postinflammatory Hypersensitivity

摘要

H_2S 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_2S-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-in-duced 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-1 beta 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_2S 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_2S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders.