The alpha(2A)-adrenoceptor subtype plays a key role in the analgesic and sedative effects of xylazine

Xylazine, the classical alpha(2)-adrenoceptor (alpha(2)-AR) agonist, is still used as an analgesic and sedative in veterinary medicine, despite its low potency and affinity for alpha(2)-ARs. Previous pharmacological studies suggested that the alpha(2A)-AR subtype plays a role in mediating the clinical effects of xylazine; however, these studies were hampered by the poor subtype-selectivity of the antagonists used and a lack of knowledge of their bioavailability in vivo. Here, we attempted to elucidate the role of the alpha(2A)-AR subtype in mediating the clinical effects of xylazine by comparing the analgesic and sedative effects of this drug in wild-type mice with those in alpha(2A)-AR functional knockout mice using the hot-plate and open field tests, respectively. Hippocampal noradrenaline turnover in both mice was also measured to evaluate the contribution of alpha(2A)-AR subtype to the inhibitory effect of xylazine on presynaptic noradrenaline release. In wild-type mice, xylazine (10 or 30 mg/kg) increased the hot-plate latency. Furthermore, xylazine (3 or 10 mg/kg) inhibited the open field locomotor activity and decreased hippocampal noradrenaline turnover. By contrast, all of these effects were abolished in alpha(2A)-AR functional knockout mice. These results indicate that the alpha(2A)-AR subtype is mainly responsible for the clinical effects of xylazine