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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 19, 2006; DOI: 10.1124/jpet.106.106435

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Received for publication April 19, 2006.
Revised July 15, 2006.
Accepted for publication July 17, 2006.

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

Eleonora Distrutti 1*, Luca Sediari 1, Andrea Mencarelli 1, Barbara Renga 1, Stefano Orlandi 1, Giuseppe Russo 1, Giuseppe Caliendo 1, Vincenzo Santagada 2, Giuseppe Cirino 2, John L. Wallace 3, Stefano Fiorucci 4

1 University of Perugia 2 University of Naples 3 University of Calgary 4 Univeristy of Perugia

* Address correspondence to: E-mail: eleonoradistrutti{at}katamail.com

Abstract

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 H2S-releasing 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 nociception and significantly inhibited CRD-induced overexpression of spinal cFOS mRNA, while mesalamine had no effect. ATB-429-induced anti-nociception was reversed by glibenclamide, a KATPchannel inhibitor. The antinociceptive effect of ATB-429 was maintained in a rodent model of post-inflammatory allodynia (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 IL-1{beta} mRNA and spinal cFOS 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 post-colitic rats. Taken together these data suggest that ATB-429 inhibits nociception induced by CRD in both healthy and post-colitic, 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.


Key words: Allodynia, Anti-inflammatory drugs, Colon, Hydrogen sulfide, Perception, irritable bowel syndrome




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