{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T01:01:50Z","timestamp":1789434110845,"version":"build-2803163510"},"reference-count":46,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":59,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2008,12]]},"abstract":"<jats:sec><jats:title>Background and purpose:<\/jats:title><jats:p>Ultra\u2010low doses of opioid receptor antagonists augment spinal morphine antinociception and block the induction of tolerance. Considering the evidence demonstrating functional and physical interactions between the opioid and \u03b1<jats:sub>2<\/jats:sub>\u2010adrenoceptors, this study investigated whether ultra\u2010low doses of \u03b1<jats:sub>2<\/jats:sub>\u2010adrenoceptor antagonists also influence spinal morphine analgesia and tolerance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach:<\/jats:title><jats:p>Effects of low doses of the competitive \u03b1<jats:sub>2<\/jats:sub>\u2010adrenoceptor antagonists\u2014atipamezole (0.08, 0.8\u2003ng), yohimbine (0.02, 2\u2003ng), mirtazapine (0.02\u2003ng) and idazoxan (0.08\u2003ng) were investigated on intrathecal morphine analgesia, as well as acute and chronic morphine antinociceptive tolerance using the rat tail flick and paw pressure tests.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results:<\/jats:title><jats:p>At doses markedly lower than those producing \u03b1<jats:sub>2<\/jats:sub>\u2010adrenoceptor blockade, atipamezole, yohimbine, mirtazapine and idazoxan, prolonged the antinociceptive effects of morphine. When co\u2010administered with repeated acute spinal injections of morphine, all four agents blocked the induction of acute tolerance. Co\u2010injection of atipamezole with morphine for 5 days inhibited the development of tolerance in a chronic treatment paradigm. Spinal administration of atipamezole also reversed established antinociceptive tolerance to morphine as indicated by the restoration of morphine antinociceptive potency. The effects of atipamezole on spinal morphine tolerance were not influenced by treatment with 6\u2010hydroxydopamine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and implications:<\/jats:title><jats:p>Low doses of competitive \u03b1<jats:sub>2<\/jats:sub>\u2010adrenoceptor antagonists can augment acute morphine analgesia and block or reverse tolerance to spinal administration of morphine. These actions are interpreted in terms of their interaction with an opioid\u2010\u03b1<jats:sub>2<\/jats:sub>\u2010adrenoceptor complex, whose activity may have a function in the genesis of analgesic tolerance.<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic>(2008)<jats:bold>155<\/jats:bold>, 1264\u20131278; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/bjp.2008.353\">10.1038\/bjp.2008.353<\/jats:ext-link>; published online 22 September 2008<\/jats:p><\/jats:sec>","DOI":"10.1038\/bjp.2008.353","type":"journal-article","created":{"date-parts":[[2008,9,22]],"date-time":"2008-09-22T09:49:40Z","timestamp":1222076980000},"page":"1264-1278","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Low doses of \u03b1<sub>2<\/sub>\u2010adrenoceptor antagonists augment spinal morphine analgesia and inhibit development of acute and chronic 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