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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 28, 2005; DOI: 10.1124/jpet.105.091595

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*Compound via MeSH
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Hazardous Substances DB
*HYDROGEN SULFIDE


Received for publication June 27, 2005.
Revised September 27, 2005.
Accepted for publication September 27, 2005.

Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels

Eleonora Distrutti 1*, Luca Sediari 2, Andrea Mencarelli 2, Barbara Renga 2, Stefano Orlandi 2, Elisabetta Antonelli 2, Fiorenza Roviezzo 3, Antonio Morelli 2, John L. Wallace 4, Giuseppe Cirino 3, Stefano Fiorucci 2

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

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

Abstract

Hydrogen sulfide (H2S) functions as a neuromodulator, but whether it modulates visceral perception and pain is unknown. Cystathionine b-synthase (CBS) and cystathionine-g-liase (CSE) mediate enzymatic generation of H2S in mammalian cells. Here we have investigated the role of H2S in modulating nociception to colorectal distension, a model that mimics some features of the irritable bowel syndrome. Four graded (0.4-1.6 ml water) colorectal distensions (CRDs) were produced in conscious rats (healthy and post-colitic) and rectal nociception assessed by measuring the behavioural response during CRD. Healthy rats were administered with NaHS (as a source of H2S), L-cysteine or vehicle. In a second model we investigated nociception to CRD in rats recovering from a chemically induced acute colitis. We found that CBS and CSE are expressed in the colon and spinal cord. Treating rats with NaHS resulted in a dose-dependent attenuation of CRD-induced nociception with the maximal effect at 60 µmol/kg (p<0.05). Administration of L-cysteine, a CSE/CBS substrate, reduced rectal sensitivity to CRD (p<0.05). NaHS-induced antinociception was reversed by glibenclamide, a KATP channel inhibitor, and N{omega}Nitro-L-arginine methyl ester hydrochloride, a nitric oxide (NO) synthase inhibitor. The antinociceptive effect of NaHS was maintained during the resolution of colon inflammation induced by intrarectal administration of a chemical irritant. In summary, these data show that H2S inhibits nociception induced by CRD in both healthy and post-colitic rats. This effect is mediated by KATP channels and NO. H2S-releasing drugs might be beneficial in treating painful intestinal disorders.


Key words: H2S, Intestinal inflammation, KATP, Nitric oxide, Visceral pain, irritable bowel syndrome


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