title: Antinociceptive properties of mixture of alpha-amyrin and beta-amyrin triterpenes: evidence for participation of protein kinase C and protein kinase A pathways.
abstract: The mixture of the two pentacyclic triterpenes alpha-amyrin and beta-amyrin, isolated from the resin of Protium kleinii and given by intraperitoneal (i.p.) or oral (p.o.) routes, caused dose-related and significant antinociception against the visceral pain in mice produced by i.p. injection of acetic acid. Moreover, i.p., p.o., intracerebroventricular (i.c.v.), or intrathecal (i.t.) administration of alpha,beta-amyrin inhibited both neurogenic and inflammatory phases of the overt nociception caused by intraplantar (i.pl.) injection of formalin. Likewise, alpha,beta-amyrin given by i.p., p.o., i.t., or i.c.v. routes inhibits the neurogenic nociception induced by capsaicin. Moreover, i.p. treatment with alpha,beta-amyrin was able to reduce the nociception produced by 8-bromo-cAMP (8-Br-cAMP) and by 12-O-tetradecanoylphorbol-13-acetate (TPA) or the hyperalgesia caused by glutamate. On the other hand, in contrast to morphine, alpha,beta-amyrin failed to cause analgesia in thermal models of pain. The antinociception caused by the mixture of compounds seems to involve mechanisms independent of opioid, alpha-adrenergic, serotoninergic, and nitrergic system mediation, since it was not affected by naloxone, prazosin, yohimbine, DL-p-chlorophenylalanine methyl ester, or L-arginine. Interestingly, the i.p. administration of alpha,beta-amyrin reduced the mechanical hyperalgesia produced by i.pl. injection of carrageenan, capsaicin, bradykinin, substance P, prostaglandin E2, 8-Br-cAMP, and TPA in rats. However, the mixture of compounds failed to alter the binding sites of [3H]bradykinin, [3H]resiniferatoxin, or [3H]glutamate in vitro. It is concluded that the mixture of triterpene alpha-amyrin and beta-amyrin produced consistent peripheral, spinal, and supraspinal antinociception in rodents, especially when assessed in inflammatory models of pain. The mechanisms involved in their action are not completely understood but seem to involve the inhibition of protein kinase A- and protein kinase C-sensitive pathways.
authors.affiliation: Department of Pharmacology, Centre of Biological Sciences, Federal University of Santa Catarina, Campus Universitario-Trindade, Bloco D-CCB, Cx. Postal: 476, CEP 88049-900, Florianópolis, SC, Brazil.
authors.forename: Michel F
authors.initials: MF
authors.lastname: Otuki
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
authors.forename: Fabiana V
authors.initials: FV
authors.lastname: Lima
authors.forename: Cristiane
authors.initials: C
authors.lastname: Meyre-Silva
authors.forename: Angela
authors.initials: A
authors.lastname: Malheiros
authors.forename: Luciane A
authors.initials: LA
authors.lastname: Muller
authors.forename: Graziela S
authors.initials: GS
authors.lastname: Cani
authors.forename: Adair R S
authors.initials: AR
authors.lastname: Santos
authors.forename: Rosendo A
authors.initials: RA
authors.lastname: Yunes
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D019342:Acetic Acid; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004224:Diterpenes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005557:Formaldehyde; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006321:Heart; D008297:Male; D051379:Mice; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement; D017933:Peripheral Nervous System / Q000502:physiology; D010812:Physical Stimulation; D011493:Protein Kinase C / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects; D013268:Stimulation, Chemical; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D004224:Diterpenes; D004338:Drug Combinations; D014315:Triterpenes; D005557:Formaldehyde; D018698:Glutamic Acid; D009828:Oleanolic Acid; C024353:resiniferatoxin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C036380:beta-amyrin; D019342:Acetic Acid; D001920:Bradykinin