title: Hydrogen sulfide donors alleviate itch secondary to the activation of type-2 protease activated receptors (PAR-2) in mice.
abstract: Hydrogen sulfide (H2S) has been highlighted as an endogenous signaling molecule and we have previously found that it can inhibit histamine-mediated itching. Pruritus is the most common symptom of cutaneous diseases and anti-histamines are the usual treatment; however, anti-histamine-resistant pruritus is common in some clinical settings. In this way, the involvement of mediators other than histamine in the context of pruritus requires new therapeutic targets. Considering that the activation of proteinase-activated receptor 2 (PAR-2) is involved in pruritus both in rodents and humans, in this study we investigated the effect of H2S donors on the acute scratching behavior mediated by PAR-2 activation in mice, as well as some of the possible pharmacological mechanisms involved. The intradermal injection of the PAR-2 peptide agonist SLIGRL-NH2(8-80nmol) caused a dose-dependent scratching that was unaffected by intraperitoneal pre-treatment with the histamine H1 antagonist pyrilamine (30mg/kg). Co-injection of SLIGRL-NH2(40nmol) with either the slow-release H2S donor GYY4137 (1 and 3nmol) or the spontaneous donor NaHS (1 and 0.3nmol) significantly reduced pruritus. Co-treatment with the KATPchannel blocker glibenclamide (200nmol) or the nitric oxide (NO) donor sodium nitroprusside (10nmol) abolished the antipruritic effects of NaHS; however, the specific soluble guanylyl cyclase inhibitor ODQ (30μg) had no significant effects. The transient receptor potential ankyrin type 1 (TRPA1) antagonist HC-030031 (20μg) significantly reduced SLIGRL-NH2-induced pruritus; however pruritus induced by the TRPA1 agonist AITC (1000nmol) was unaffected by NaHS. Based on these data, we conclude that pruritus secondary to PAR-2 activation can be reduced by H2S, which acts through KATPchannel opening and involves NO in a cyclic guanosine monophosphate (cGMP)-independent manner. Furthermore, TRPA1 receptors mediate the pruritus induced by activation of PAR-2, but H2S does not interfere with this pathway. These results provide additional support for the development of new therapeutical alternatives, mainly intended for treatment of pruritus in patients unresponsive to anti-histamines.
authors.affiliation: Dept. of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-900, SP, Brazil.
authors.forename: S A
authors.initials: SA
authors.lastname: Coavoy-Sánchez
authors.affiliation: Dept. of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-900, SP, Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Rodrigues
authors.affiliation: Dept. of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-900, SP, Brazil.
authors.forename: S A
authors.initials: SA
authors.lastname: Teixeira
authors.affiliation: Dept. of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-900, SP, Brazil.
authors.forename: A G
authors.initials: AG
authors.lastname: Soares
authors.affiliation: Biosciences, College of Life and Environmental Science, University of Exeter, Exeter, UK; University of Exeter Medical School, Exeter, UK.
authors.forename: R
authors.initials: R
authors.lastname: Torregrossa
authors.affiliation: University of Exeter Medical School, Exeter, UK.
authors.forename: M E
authors.initials: ME
authors.lastname: Wood
authors.affiliation: University of Exeter Medical School, Exeter, UK.
authors.forename: M
authors.initials: M
authors.lastname: Whiteman
authors.affiliation: Dept. of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-900, SP, Brazil.
authors.forename: S K P
authors.initials: SKP
authors.lastname: Costa
authors.affiliation: Dept. of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-900, SP, Brazil. Electronic address: muscara@usp.br.
authors.forename: M N
authors.initials: MN
authors.lastname: Muscará
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005905:Glyburide / Q000493:pharmacokinetics; D006632:Histamine / Q000378:metabolism; D006633:Histamine Antagonists / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D017879:Isothiocyanates / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D011537:Pruritus / Q000188:drug therapy* / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000378:metabolism
chemical_list: C529376:GYY 4137; D006633:Histamine Antagonists; D017879:Isothiocyanates; D009025:Morpholines; D009842:Oligopeptides; D009946:Organothiophosphorus Compounds; D044464:Receptor, PAR-2; D050051:Transient Receptor Potential Channels; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; D009599:Nitroprusside; C041942:2,3,4-tri-O-acetylarabinopyranosyl isothiocyanate; D006632:Histamine; D005905:Glyburide; D006862:Hydrogen Sulfide
keywords: Hydrogen sulfide; Mouse; Protease-activated receptor 2; Pruritus