Antinociceptive properties of mixture of alpha-amyrin and beta-amyrin triterpenes: evidence for participation of protein kinase C and protein kinase A pathways

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 aceti...

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Published in:The Journal of pharmacology and experimental therapeutics 2005-04, Vol.313 (1), p.310-318
Main Authors: Otuki, Michel F, Ferreira, Juliano, Lima, Fabiana V, Meyre-Silva, Cristiane, Malheiros, Angela, Muller, Luciane A, Cani, Graziela S, Santos, Adair R S, Yunes, Rosendo A, Calixto, João B
Format: Article
Language:English
Subjects:
Acetic Acid
Analgesics - pharmacology
Animals
Bradykinin - metabolism
Cyclic AMP-Dependent Protein Kinases - metabolism
Diterpenes - metabolism
Dose-Response Relationship, Drug
Drug Combinations
Formaldehyde
Glutamic Acid - metabolism
Glutamic Acid - pharmacology
Heart
Male
Mice
Oleanolic Acid - analogs & derivatives
Oleanolic Acid - pharmacology
Pain - chemically induced
Pain - drug therapy
Pain Measurement
Peripheral Nervous System - physiology
Physical Stimulation
Protein Kinase C - metabolism
Psychomotor Performance - drug effects
Rats
Rats, Wistar
Reaction Time - drug effects
Spinal Cord - drug effects
Stimulation, Chemical
Triterpenes - pharmacology
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Summary: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.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.104.071779