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

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.