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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Evidence That Hydrogen Sulfide Exerts Antinociceptive Effects in the Gastrointestinal Tract by Activating K_ATP Channels

Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia, University of Perugia, Perugia, Italy (E.D., A.Me., L.S., B.R., S.O., E.A., A.Mo., S.F.); Dipartimento di Farmacologia Sperimentale, University of Naples, Napoli, Italy (G.C., F.R.); and Mucosal Inflammation Research Group, University of Calgary, Calgary, Alberta, Canada (J.L.W.)

Hydrogen sulfide (H₂S) functions as a neuromodulator, but whether it modulates visceral perception and pain is unknown. Cystathionine -synthase (CBS) and cystathionine--lyase (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 of water) colorectal distensions (CRDs) were produced in conscious rats (healthy and postcolitic), and rectal nociception was assessed by measuring the behavioral response during CRD. Healthy rats were administered with sodium hydrogen sulfide (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 ATP-sensitive K⁺ (K_ATP) channel inhibitor, and N-nitro-L-arginine methyl ester hydrochloride (L-NAME), 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 postcolitic rats. This effect is mediated by K_ATP channels and NO. H₂S-releasing drugs might be beneficial in treating painful intestinal disorders.

Address correspondence to: Dr. Eleonora Distrutti, University of Perugia, Clinica di Gastroenterologia, Policlinico Monteluce, Via Enrico Dal Pozzo, 06122 Perugia, Italy. E-mail: eleonoradistrutti{at}katamail.com

This article has been cited by other articles:

				E. Distrutti, L. Sediari, A. Mencarelli, B. Renga, S. Orlandi, G. Russo, G. Caliendo, V. Santagada, G. Cirino, J. L. Wallace, et al. 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 J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 447 - 458. [Abstract] [Full Text] [PDF]