Abstract
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.
Footnotes
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J.L.W. is supported by grants from the Canadian Institutes of Health Research and holds a Canada Research Chair in Inflammation Research and an Alberta Heritage Foundation for Medical Research Scientist award. G.C., V.S., G.C., J.L.W., and S.F. hold shares in Antibe Therapeutics Inc., the manufacturer of ATB-429.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.106435.
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ABBREVIATIONS: IBS, irritable bowel syndrome; MPO, myeloperoxidase; IBD, irritable bowel disease; ABT-429, 5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester; KATP, ATP-sensitive K+; CBS, cystathionine-β synthase; CSE, cystathionine-γ lyase; CRD, colorectal distension; ADT-OH, 5-p-hydroxyphenyl-1,2-dithione-3-thione; AWR, abdominal withdrawal reflex; TNBS, trinitrobenzene sulfonic acid; SAOB, sulfide antioxidant buffer; RT-PCR, reverse transcription-polymerase chain reaction; COX, cyclooxygenase; TNF, tumor necrosis factor; IL, interleukin; cNOS, constitutive NO synthase; CGRP, calcitonin gene-related peptide; TAC, takikinin; i.p., intraperitoneal; i.v. intravenous.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received April 18, 2006.
- Accepted July 17, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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