title: Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels.
abstract: Hydrogen sulfide (H(2)S) functions as a neuromodulator, but whether it modulates visceral perception and pain is unknown. Cystathionine beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) mediate enzymatic generation of H(2)S in mammalian cells. Here we have investigated the role of H(2)S 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 H(2)S), 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 micromol/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(omega)-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 H(2)S inhibits nociception induced by CRD in both healthy and postcolitic rats. This effect is mediated by K(ATP) channels and NO. H(2)S-releasing drugs might be beneficial in treating painful intestinal disorders.
authors.affiliation: University of Perugia, Clinica di Gastroenterologia, Policlinico Monteluce, Via Enrico Dal Pozzo, 06122 Perugia, Italy. eleonoradistrutti@katamail.com
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.forename: Luca
authors.initials: L
authors.lastname: Sediari
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Stefano
authors.initials: S
authors.lastname: Orlandi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Antonelli
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Roviezzo
authors.forename: Antonio
authors.initials: A
authors.lastname: Morelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000819:agonists*; D000393:Air Pollutants / Q000494:pharmacology*; D000700:Analgesics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003092:Colitis / Q000523:psychology; D003106:Colon / Q000502:physiology; D003541:Cystathionine beta-Synthase / Q000037:antagonists & inhibitors; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors; D004064:Digestive System / Q000187:drug effects*; D004106:Dilatation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000235:genetics; D005905:Glyburide / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000097:blood / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D054086:KATP Channels; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010147:Pain Measurement / Q000187:drug effects; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists*; D051381:Rats; D017208:Rats, Wistar; D012007:Rectum / Q000502:physiology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000393:Air Pollutants; D000700:Analgesics; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel; D019001:Nitric Oxide Synthase; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester; D006862:Hydrogen Sulfide