Determination of adrenergic and imidazoline receptor involvement in augmentation of morphine and oxycodone analgesia by clonidine and BMS182874

Pharmacology. 2009;83(1):45-58. doi: 10.1159/000178812. Epub 2008 Dec 4.


Background: Numerous agents have been demonstrated to potentiate morphine analgesia, including clonidine (alpha(2)-adrenergic and I(1)-imidazoline receptor agonist) and BMS182874 (endothelin-A, ET(A,) receptor antagonist). ET has been shown to affect pharmacological actions of clonidine. The present study was conducted to determine whether alpha(2)-adrenergic and/or I(1)-imidazoline receptors are involved in the augmentation of morphine and oxycodone analgesia by clonidine and BMS182874.

Methods: Analgesic tail flick latencies were measured in rats at various time intervals, and were converted to AUC(0)-->(360 min).

Results: It was found that clonidine produced mild analgesia, while BMS182874 did not have any analgesic effect. Clonidine (p = 0.015) and BMS182874 (p = 0.009) enhanced the analgesic action of morphine and oxycodone. Clonidine- or BMS182874-induced increases in the analgesic effect of morphine were not inhibited by idazoxan (I(1)-imidazoline receptor antagonist), while increases in the analgesic effect of oxycodone were blocked by idazoxan. Yohimbine (alpha(2)-adrenergic receptor antagonist) blocked the clonidine-induced potentiation of analgesic effect of morphine (p = 0.036) and oxycodone (p = 0.0167), while yohimbine did not affect BMS182874-induced potentiation of the analgesic effect of morphine or oxycodone.

Conclusions: This is the first report showing that clonidine and BMS182874 augment oxycodone analgesia. Results suggest that alpha(2)-adrenergic receptors are involved in clonidine-induced, but not in the BMS182874-induced, potentiation of the analgesic effects of morphine or oxycodone, and that I(1)-imidazoline receptors are involved in the potentiation of oxycodone analgesia, but not morphine analgesia, by clonidine and BMS182874.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Agonists / pharmacology
  • Analgesics, Opioid / pharmacology
  • Animals
  • Area Under Curve
  • Clonidine / pharmacology*
  • Dansyl Compounds / pharmacology*
  • Disease Models, Animal
  • Drug Synergism
  • Idazoxan / pharmacology
  • Imidazoline Receptors / drug effects
  • Imidazoline Receptors / metabolism
  • Male
  • Morphine / pharmacology*
  • Oxycodone / pharmacology*
  • Pain / drug therapy
  • Pain Measurement
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-2 / drug effects
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Time Factors
  • Yohimbine / pharmacology


  • Adrenergic alpha-Agonists
  • Analgesics, Opioid
  • Dansyl Compounds
  • Imidazoline Receptors
  • Receptors, Adrenergic, alpha-2
  • imidazoline I1 receptors
  • 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide
  • Yohimbine
  • Morphine
  • Oxycodone
  • Clonidine
  • Idazoxan