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

  1. Eleonora Distrutti,
  2. Luca Sediari,
  3. Andrea Mencarelli,
  4. Barbara Renga,
  5. Stefano Orlandi,
  6. Elisabetta Antonelli,
  7. Fiorenza Roviezzo,
  8. Antonio Morelli,
  9. Giuseppe Cirino,
  10. John L. Wallace and
  11. Stefano Fiorucci
  1. 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.)
  1. 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

Abstract

Hydrogen sulfide (H2S) functions as a neuromodulator, but whether it modulates visceral perception and pain is unknown. Cystathionineβ -synthase (CBS) and cystathionine-γ-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+ (KATP) channel inhibitor, and Nω-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 KATP channels and NO. H2S-releasing drugs might be beneficial in treating painful intestinal disorders.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.105.091595.

  • ABBREVIATIONS: NO, nitric oxide; H2S, hydrogen sulfide; CBS, cystathionine β-synthase; CSE, cystathionine-γ-lyase; CRD, colorectal distension; MPO, myeloperoxidase; NaHS, sodium hydrogen sulfide; l-NAME, Nω-nitro-l-arginine methyl ester hydrochloride; IBS, irritable bowel syndrome; AWR, abdominal withdrawal reflex; TNBS, trinitrobenzene sulfonic acid; SAOB, sulfide antioxidant buffer; RT, reverse transcription; PCR, polymerase chain reaction.

    • Received June 25, 2005.
    • Accepted September 27, 2005.
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  1. Published online before print September 28, 2005, doi: 10.1124/jpet.105.091595 JPET January 2006 vol. 316 no. 1 325-335
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