Involvement of α2-adrenoceptors, imidazoline, and endothelin-A receptors in the effect of agmatine on morphine and oxycodone-induced hypothermia in mice

Potentiation of opioid analgesia by endothelin-A (ETA) receptor antagonist, BMS182874, and imidazoline receptor/a2-adrenoceptor agonists such as clonidine and agmatine are well known. It is also known that agmatine blocks morphine hyperthermia in rats. However, the effect of agmatine on morphine or oxycodone hypothermia in mice is unknown. The present study was carried out to study the role of a2-adrenoceptors, imidazoline, and ETA receptors in morphine and oxycodone hypothermia in mice. Body temperature was determined over 6 h in male Swiss Webster mice treated with morphine, oxycodone, agmatine, and combination of agmatine with morphine or oxycodone. Yohimbine, idazoxan, and BMS182874 were used to determine involvement of a2-adrenoceptors, imidazoline, and ETA receptors, respectively. Morphine and oxycodone produced significant hypothermia that was not affected by a2-adrenoceptor antagonist yohimbine, imidazoline receptor/a2 adrenoceptor antagonist idazoxan, or ETA receptor antagonist, BMS182874. Agmatine did not produce hypothermia; however, it blocked oxycodone but not morphine-induced hypothermia. Agmatine-induced blockade of oxycodone hypothermia was inhibited by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared with yohimbine. Combined administration of BMS182874 and agmatine did not produce changes in body temperature in mice. However, when BMS182874 was administered along with agmatine and oxycodone, it blocked agmatine-induced reversal of oxycodone hypothermia. This is the first report demonstrating that agmatine does not affect morphine hypothermia in mice, but reverses oxycodone hypothermia. Imidazoline receptors and a2-adrenoceptors are involved in agmatine-induced reversal of oxycodone hypothermia. Our findings also suggest that ETA receptors may be involved in blockade of oxycodone hypothermia by agmatine.