title: Kaurenoic acid from Sphagneticola trilobata Inhibits Inflammatory Pain: effect on cytokine production and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway.
abstract: Kaurenoic acid [ent-kaur-16-en-19-oic acid (1)] is a diterpene present in several plants including Sphagneticola trilobata. The only documented evidence for its antinociceptive effect is that it inhibits the writhing response induced by acetic acid in mice. Therefore, the analgesic effect of 1 in different models of pain and its mechanisms in mice were investigated further. Intraperitoneal and oral treatment with 1 dose-dependently inhibited inflammatory nociception induced by acetic acid. Oral treatment with 1 also inhibited overt nociception-like behavior induced by phenyl-p-benzoquinone, complete Freund's adjuvant (CFA), and both phases of the formalin test. Compound 1 also inhibited acute carrageenin- and PGE(2)-induced and chronic CFA-induced inflammatory mechanical hyperalgesia. Mechanistically, 1 inhibited the production of the hyperalgesic cytokines TNF-α and IL-1β. Furthermore, the analgesic effect of 1 was inhibited by l-NAME, ODQ, KT5823, and glybenclamide treatment, demonstrating that such activity also depends on activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway, respectively. These results demonstrate that 1 exhibits an analgesic effect in a consistent manner and that its mechanisms involve the inhibition of cytokine production and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway.
authors.affiliation: Departamento de Ciências Patológicas-Centro de Ciências Biológicas,  Universidade Estadual de Londrina , 86051990 Londrina, Brazil.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Mizokami
authors.forename: Nilton S
authors.initials: NS
authors.lastname: Arakawa
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Ambrosio
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zarpelon
authors.forename: Rubia
authors.initials: R
authors.lastname: Casagrande
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D019342:Acetic Acid / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D019659:Asteraceae / Q000737:chemistry*; D002227:Carbazoles / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects*; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000494:pharmacology; D005620:Freund's Adjuvant / Q000009:adverse effects / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy*; D007274:Injections, Intraperitoneal; D016209:Interleukin-8 / Q000187:drug effects; D054086:KATP Channels / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced* / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
chemical_list: D002227:Carbazoles; D016207:Cytokines; D004224:Diterpenes; D016209:Interleukin-8; D054086:KATP Channels; D014409:Tumor Necrosis Factor-alpha; C073601:KT 5823; D005557:Formaldehyde; C051436:kaurenoic acid; D005620:Freund's Adjuvant; D017869:Cyclic GMP-Dependent Protein Kinases; D019342:Acetic Acid; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester