title: The analgesic efficacy of partial opioid agonists is increased in mice with targeted inactivation of the alpha2A-adrenoceptor gene.
abstract: 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<0.001 for both). The effects of alpha(2A)-KO were mimicked by pretreatment of wild-type control mice with the alpha(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 alpha(2A)-KO. Antagonists of alpha(2A)-adrenoceptors may offer a novel mechanism to augment the antinociceptive actions of partial opioid agonists.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Turku, FI-20520 Turku, Finland.
authors.forename: Umit Kazim
authors.initials: UK
authors.lastname: Ozdoğan
authors.forename: Janne
authors.initials: J
authors.lastname: Lähdesmäki
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
mesh_terms: D018674:Adrenergic Antagonists / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011957:Receptors, Opioid / Q000819:agonists*
chemical_list: C547769:Adra2a protein, mouse; D018674:Adrenergic Antagonists; D000701:Analgesics, Opioid; D018341:Receptors, Adrenergic, alpha-2; D011957:Receptors, Opioid