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Low doses of α 2 ‐adrenoceptor antagonists augment spinal morphine analgesia and inhibit development of acute and chronic tolerance
Author(s) -
Milne B,
Sutak M,
Cahill C M,
Jhamandas K
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.353
Subject(s) - morphine , yohimbine , atipamezole , idazoxan , medicine , pharmacology , nociception , opioid , tail flick test , analgesic , (+) naloxone , anesthesia , drug tolerance , neuropathic pain , clonidine , antagonist , receptor , prazosin , blood pressure , heart rate , medetomidine
Background and purpose: Ultra‐low 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 α 2 ‐adrenoceptors, this study investigated whether ultra‐low doses of α 2 ‐adrenoceptor antagonists also influence spinal morphine analgesia and tolerance. Experimental approach: Effects of low doses of the competitive α 2 ‐adrenoceptor antagonists—atipamezole (0.08, 0.8 ng), yohimbine (0.02, 2 ng), mirtazapine (0.02 ng) and idazoxan (0.08 ng) were investigated on intrathecal morphine analgesia, as well as acute and chronic morphine antinociceptive tolerance using the rat tail flick and paw pressure tests. Key results: At doses markedly lower than those producing α 2 ‐adrenoceptor blockade, atipamezole, yohimbine, mirtazapine and idazoxan, prolonged the antinociceptive effects of morphine. When co‐administered with repeated acute spinal injections of morphine, all four agents blocked the induction of acute tolerance. Co‐injection 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‐hydroxydopamine. Conclusions and implications: Low doses of competitive α 2 ‐adrenoceptor 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‐α 2 ‐adrenoceptor complex, whose activity may have a function in the genesis of analgesic tolerance. British Journal of Pharmacology (2008) 155 , 1264–1278; doi: 10.1038/bjp.2008.353 ; published online 22 September 2008