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

Abstract

Potentiation of opioid analgesia by endothelin‐A (ETA) receptor antagonist, BMS182874, and imidazoline receptor/α₂‐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 α₂‐adrenoceptors, imidazoline and ET_A receptors in morphine and oxycodone hypothermia in mice.

Body temperature was determined over six hours 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 α₂‐adrenoceptors, imidazoline and ET_A receptors, respectively.

Morphine and oxycodone produced significant hypothermia which was not affected by α₂‐adrenoceptor antagonist yohimbine, imidazoline receptor/α₂ adrenoceptor antagonist idazoxan, or ET_A 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 to 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 α₂‐adrenoceptors are involved in agmatine‐induced reversal of oxycodone hypothermia. Our findings also suggest that ET_A receptors may be involved in blockade of oxycodone hypothermia by agmatine.