α 2A -Adrenoceptors mediate the antinociceptive effects of α 2 -adrenoceptor agonists in mice, and analgesic synergism between noradrenergic and opioidergic mechanisms has been reported to be lacking in mice devoid of functional α 2A -adrenoceptors. We investigated whether the antinociceptive actions of opioid agonists with different efficacy would be altered in mice with targeted inactivation of the α 2A -adrenoceptor gene (α 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 α 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 α 2A -KO and 22±2% of MPE in control mice; prolongation of hot-plate latency was 93±5% of MPE in α 2A -KO mice and 8±2% of MPE in the controls (P<0.001 for both). The effects of α 2A -KO were mimicked by pretreatment of wild-type control mice with the α 2 -adrenoceptor antagonists, atipamezole and yohimbine; the apparent efficacy of tramadol and buprenorphine now approached that of morphine and fentanyl. Other behavioural effects of the tested opioid agonists were not similarly influenced by α 2A -KO. Antagonists of α 2A -adrenoceptors may offer a novel mechanism to augment the antinociceptive actions of partial opioid agonists.