title: Dual role of hydrogen sulfide in mechanical inflammatory hypernociception.
abstract: Hydrogen sulfide (H(2)S) is an endogenous gas involved in several biological functions, including modulation of nociception. However, the mechanisms involved in such modulation are not fully elucidated. The present study demonstrated that the pretreatment of mice with PAG, a H(2)S synthesis inhibitor, reduced LPS-induced mechanical paw hypernociception. This inhibition of hypernociception was associated with the prevention of neutrophil recruitment to the plantar tissue. Conversely, PAG had no effect on LPS-induced production of the hypernociceptive cytokines, TNF-alpha, IL-1beta and CXCL1/KC and on hypernociception induced by PGE(2), a directly acting hypernociceptive mediator. In contrast with the pro-nociceptive role of endogenous H(2)S, systemic administration of NaHS, a H(2)S donor, reduced LPS-induced mechanical hypernociception in mice. Moreover, this treatment inhibited mechanical hypernociception induced by PGE(2), suggesting a direct effect of H(2)S on nociceptive neurons. The antinociceptive mechanism of exogenous H(2)S depends on K((ATP))(+) channels since the inhibition of PGE(2) hypernociception by NaHS was prevented by glibenclamide (K((ATP))(+) channel blocker). Finally, NaHS did not alter the thermal nociceptive threshold in the hot-plate test, confirming that its effect is mainly peripheral. Taken together, these results suggest that H(2)S has a dual role in inflammatory hypernociception: 1. an endogenous pro-nociceptive effect due to up-regulation of neutrophil migration, and 2. an antinociceptive effect by direct blockade of nociceptor sensitization modulating K((ATP))(+) channels.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Daniela
authors.initials: D
authors.lastname: Dal-Secco
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Ana T
authors.initials: AT
authors.lastname: Guerrero
authors.forename: Guilherme R
authors.initials: GR
authors.lastname: Souza
authors.forename: Silvio M
authors.initials: SM
authors.lastname: Vieira
authors.forename: Celina M
authors.initials: CM
authors.lastname: Lotufo
authors.forename: Alberto F
authors.initials: AF
authors.lastname: Neto
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007249:Inflammation / Q000503:physiopathology*; D054086:KATP Channels / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology; D010146:Pain / Q000503:physiopathology* / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000700:Analgesics; D054086:KATP Channels; D006862:Hydrogen Sulfide