The analgesic efficacy of partial opioid agonists is increased in mice with targeted inactivation of the alpha2A-adrenoceptor gene

Alpha(2A)-Adrenoceptors mediate the antinociceptive effects of alpha(2)-adrenoceptor agonists in mice, and analgesic synergism between noradrenergic and opioidergic mechanisms has been reported to be lacking in mice devoid of functional alpha(2A)-adrenoceptors. We investigated whether the antinociceptive actions of opioid agonists with different efficacy would be altered in mice with targeted inactivation of the alpha(2A)-adrenoceptor gene (alpha(2A)-KO mice). The antinociceptive effects of fentanyl, morphine, buprenorphine and tramadol were assessed using conventional tail-flick and hot-plate assays. Antinociceptive responses to fentanyl were unaltered in the alpha(2A)-KO animals. Morphine analgesia was slightly accentuated in the tail-flick test. The naloxone-sensitive antinociceptive responses to both tested weak partial agonists were very markedly accentuated in both tests. For example, after 40 mg/kg tramadol administration, the tramadol-induced prolongation of tail-flick latency was 86+/-6% of the maximal possible effect (MPE) in alpha(2A)-KO and 22+/-2% of MPE in control mice; prolongation of hot-plate latency was 93+/-5% of MPE in alpha(2A)-KO mice and 8+/-2% of MPE in the controls (P