title: Low doses of alpha 2-adrenoceptor antagonists augment spinal morphine analgesia and inhibit development of acute and chronic tolerance.
abstract: OBJECTIVE
  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 alpha(2)-adrenoceptors, this study investigated whether ultra-low doses of alpha(2)-adrenoceptor antagonists also influence spinal morphine analgesia and tolerance.
  
  
  METHODS
  Effects of low doses of the competitive alpha(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.
  
  
  RESULTS
  At doses markedly lower than those producing alpha(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
  Low doses of competitive alpha(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-alpha(2)-adrenoceptor complex, whose activity may have a function in the genesis of analgesic tolerance.
authors.affiliation: Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Milne
authors.forename: M
authors.initials: M
authors.lastname: Sutak
authors.forename: C M
authors.initials: CM
authors.lastname: Cahill
authors.forename: K
authors.initials: K
authors.lastname: Jhamandas
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D019329:Idazoxan / Q000008:administration & dosage / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008803:Mianserin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000078785:Mirtazapine; D009020:Morphine / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013131:Spine; D015016:Yohimbine / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; C050701:atipamezole; D008803:Mianserin; D015016:Yohimbine; D009020:Morphine; D000078785:Mirtazapine; D019329:Idazoxan