Probable involvement of α2C-adrenoceptor subtype and endogenous opioid peptides in the peripheral antinociceptive effect induced by xylazine

Xylazine is an α2-adrenoceptor agonist extensively used in veterinary and animal experimentation. Evidence exists that α2-adrenoceptor agonists can activate opioid receptors via endogenous opioid release. Considering this idea and the multiple α2 subtypes currently known (α2A, α2B, α2C and α2D), the aim of this study was to investigate which α2 receptor subtype mediates xylazine-induced peripheral antinociception and possible opioid receptor and endogenous opioid involvement. The rat pressure test was used; the hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2 µg). Xylazine was administered locally (25, 50 and 100 µg) into the right hind paw of Wistar rat alone and after either α2-adrenoceptor antagonist yohimbine (5, 10 and 20 µg/paw), the α2 antagonists to α2A, α2B, α2C and α2D subtypes (BRL 44 480, imiloxan, rauwolscine and RX 821002; 20 µg/paw, respectively) the opioid receptor antagonist naloxone (12.5, 25 and 50 µg) and the enkephalinase inhibitor bestatin (400 µg/paw). Intraplantar injection of xylazine (50 and 100 µg) induced peripheral antinociception; however, a dose of 25 µg/paw did not significantly reduce the hyperalgesic effect. Yohimbine, rauwolscine and naloxone prevented action of xylazine 100 µg/paw. BRL 44 480, imiloxan and RX 821002 were ineffective in blocking xylazine antinociception. Bestatin (400 µg/paw) potentiated the antinociceptive effect of xylazine 25 µg/paw. The present results provide evidence that the peripheral antinociceptive effect of xylazine probably results from activation of α2C-adrenoceptors and also by the release of endogenous opioids that act on their receptors.