Potentiation of oxycodone antinociception in mice by agmatine and BMS182874 via an imidazoline I2 receptor-mediated mechanism.

Abstract The potentiation of oxycodone antinociception by BMS182874 (endothelin-A (ET A ) receptor antagonist) and agmatine (imidazoline receptor/α 2 -adrenoceptor agonist) is well-documented. It is also known that imidazoline receptors but not α 2 -adrenoceptors are involved in potentiation of oxycodone antinociception by agmatine and BMS182874 in mice. However, the involvement of specific imidazoline receptor subtypes (I 1 , I 2 , or both) in this interaction is not clearly understood. The present study was conducted to determine the involvement of imidazoline I 1 and I 2 receptors in agmatine- and BMS182874-induced potentiation of oxycodone antinociception in mice. Antinociceptive (tail flick and hot-plate) latencies were determined in male Swiss Webster mice treated with oxycodone, agmatine, BMS182874, and combined administration of oxycodone with agmatine or BMS182874. Efaroxan (imidazoline I 1 receptor antagonist) and BU224 (imidazoline I 2 receptor antagonist) were used to determine the involvement of I 1 and I 2 imidazoline receptors, respectively. Oxycodone produced significant antinociceptive response in mice which was not affected by efaroxan but was blocked by BU224. Agmatine-induced potentiation of oxycodone antinociception was blocked by BU224 but not by efaroxan. Similarly, BMS182874-induced potentiation of oxycodone antinociception was blocked by BU224 but not by efaroxan. This is the first report demonstrating that BMS182874- or agmatine-induced enhancement of oxycodone antinociception is blocked by BU224 but not by efaroxan. We conclude that imidazoline I 2 receptors but not imidazoline I 1 receptors are involved in BMS182874- and agmatine-induced potentiation of oxycodone antinociception in mice.