title: Mechanisms involved in the antinociceptive effects of 7-hydroxycoumarin.
abstract: 7-Hydroxycoumarin (umbelliferone, 1), the main metabolite of coumarin, has been reported to produce potent antinociceptive effects in animal models of pain. However, the biochemical events involved in antinociception mediated by 1 are currently not well understood. In the present study, the mechanisms by which 1 exerts its pharmacological actions were investigated. Acute pretreatment of mice with 1 produced a long-lasting antinociceptive effect against complete Freund's adjuvant (CFA)-induced hyperalgesia. The subchronic administration of 1 inhibited CFA-induced hyperalgesia and paw edema, while it did not cause any apparent toxicity. Another set of experiments showed that 1 inhibited carrageenan-induced mechanical hyperalgesia, but not mechanical hyperalgesia induced by prostaglandin E(2) (PGE(2)), suggesting that it acts upstream of PGE(2.) Treatment with 1 was able to prevent the plantar tissue neutrophil influx induced by local inflammatory stimuli. In addition, 1 exhibited inhibitory effects on the release of hyperalgesic cytokines (TNF-α and IL-1β) and the production of PGE(2), a directly acting hyperalgesic mediator. The present results suggest that the antinociceptive effect of 1 is correlated with the inhibition of neutrophil migration, cytokine release, and PGE(2) production and are supportive of the further investigation of the therapeutic potential of 1 to control inflammatory pain.
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brazil.
authors.forename: Flávia Oliveira
authors.initials: FO
authors.lastname: de Lima
authors.forename: Fabiana Regina
authors.initials: FR
authors.lastname: Nonato
authors.forename: Ricardo David
authors.initials: RD
authors.lastname: Couto
authors.forename: José Maria
authors.initials: JM
authors.lastname: Barbosa Filho
authors.forename: Xirley Pereira
authors.initials: XP
authors.lastname: Nunes
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ribeiro dos Santos
authors.forename: Milena Botelho Pereira
authors.initials: MB
authors.lastname: Soares
authors.forename: Cristiane Flora
authors.initials: CF
authors.lastname: Villarreal
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001938:Brazil; D015232:Dinoprostone / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005620:Freund's Adjuvant / Q000494:pharmacology; D051379:Mice; D023421:Models, Animal; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014468:Umbelliferones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000700:Analgesics; D014409:Tumor Necrosis Factor-alpha; D014468:Umbelliferones; C031477:7-hydroxycoumarin; D005620:Freund's Adjuvant; D015232:Dinoprostone