α2-Adrenoceptor agonist induces peripheral antinociception via the endocannabinoid system

Background: Xylazine is an ? adrenoceptor agonist that is extensively used in veterinary medicine and animal experimentation procedures to produce analgesia, sedation and muscle relaxation without causing general anesthesia. Considering the lack of knowledge of the mechanisms involved in peripheral antinociception induced by xylazine and the potential interactions between the adrenergic and endocannabinoid systems, the present study investigated the contribution of the latter system in the mechanism of xylazine. Methods: The rat paw pressure test, in which hyperalgesia was induced by the intraplantar injection of prostaglandin E, was performed. Results: Xylazine administered via an intraplantar injection (25, 50 and 100 ?g) induced a peripheral antinociceptive effect against prostaglandin E (2 ?g)-induced hyperalgesia. This effect was blocked by treatment with the selective CB cannabinoid antagonist AM251 (20, 40 and 80 ?g) but not by the selective CB cannabinoid antagonist AM630 (100 ?g). The anandamide reuptake inhibitor VDM11 (2.5 ?g) intensified the peripheral antinociceptive effect of a submaximal dose of xylazine (25 ?g), and the inhibitor of endocannabinoid enzymatic hydrolysis, MAFP (0.5 ?g), showed a tendency towards this same effect. In addition, liquid-chromatography mass spectrometric analysis indicated that xylazine (100 ?g) treatment was associated with an increase in anandamide levels in the rat paws treated with PGE. Conclusions: The present results provides evidence that the peripheral antinociceptive effect of the ? adrenoceptor agonist xylazine probably results from anandamide release and subsequent CB cannabinoid receptor activation.