Probable involvement of alpha(2C)-adrenoceptor subtype and endogenous opioid peptides in the peripheral antinociceptive effect induced by xylazine

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