PT  - JOURNAL ARTICLE
AU  - Eleonora Distrutti
AU  - Luca Sediari
AU  - Andrea Mencarelli
AU  - Barbara Renga
AU  - Stefano Orlandi
AU  - Giuseppe Russo
AU  - Giuseppe Caliendo
AU  - Vincenzo Santagada
AU  - Giuseppe Cirino
AU  - John L. Wallace
AU  - Stefano Fiorucci
TI  - 5-Amino-2-hydroxybenzoic Acid 4-(5-Thioxo-5<em>H</em>-[1,2]dithiol-3yl)-phenyl Ester (ATB-429), a Hydrogen Sulfide-Releasing Derivative of Mesalamine, Exerts Antinociceptive Effects in a Model of Postinflammatory Hypersensitivity
AID  - 10.1124/jpet.106.106435
DP  - 2006 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 447--458
VI  - 319
IP  - 1
4099  - http://jpet.aspetjournals.org/content/319/1/447.short
4100  - http://jpet.aspetjournals.org/content/319/1/447.full
SO  - J Pharmacol Exp Ther2006 Oct 01; 319
AB  - 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 H2S-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+ (KATP) 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-1β 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 H2S 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 KATP channel-mediated mechanism. This study provides evidence that H2S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders. The American Society for Pharmacology and Experimental Therapeutics