Determination of Adrenergic and Imidazoline Receptor Involvement in Augmentation of Morphine and Oxycodone Analgesia by Clonidine and BMS182874

Abstract

Background: Numerous agents have been demonstrated to potentiate morphine analgesia, including clonidine (α₂-adrenergic and I₁-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 α₂-adrenergic and/or I₁-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 AUC₀→_{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 (I₁-imidazoline receptor antagonist), while increases in the analgesic effect of oxycodone were blocked by idazoxan. Yohimbine (α₂-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 α₂-adrenergic receptors are involved in clonidine-induced, but not in the BMS182874-induced, potentiation of the analgesic effects of morphine or oxycodone, and that I₁-imidazoline receptors are involved in the potentiation of oxycodone analgesia, but not morphine analgesia, by clonidine and BMS182874.