Background: Meperidine proved to be more effective in treatment of shivering than equianalgesic doses of other opioids, especially pure -agonists. Further, meperidine has well known nonopioid actions including agonistic effects at ␣ 2 -adrenoceptors in vitro. Accordingly, the authors investigated nonopioid receptor-mediated effects of meperidine on thermoregulation using a mice model of nonshivering thermogenesis. To differentiate conceivable ␣ 2 -adrenoceptor subtype specific interactions the authors analyzed wild-type mice and knock-out mice with deletion of the ␣ 2A -, ␣ 2B -, or ␣ 2C -adrenoceptor.Methods: Ten mice per group (n ؍ 60) were injected with saline, meperidine (20 mg/kg), saline plus naloxone (125 g/ kg), meperidine plus naloxone, fentanyl (50 g/kg) plus naloxone, or meperidine plus atipamezole (2 mg/kg) intraperitoneally. Each mouse was subjected to the six different treatments. Then they were positioned into a plexiglas chamber where rectal temperature and mixed expired carbon dioxide were measured while whole body cooling was performed. Maximum response intensity and thermoregulatory threshold temperature of nonshivering thermogenesis were analyzed.Results: Meperidine decreased the thermoregulatory threshold temperature in wild-type mice and ␣ 2B -and ␣ 2C -adrenoceptor knock-out mice. This effect ended after injection of the ␣ 2 -adrenoceptor antagonist atipamezole. In wild-type and ␣ 2B -adrenoceptor knock-out mice, the decrease of thermoregulatory threshold was not reversible by administration of the opioid receptor antagonist naloxone. In contrast, in ␣ 2A -adrenoceptor knock-out mice, no decline of thermoregulatory threshold following meperidine injection was detectable. Maximum response intensity of nonshivering thermogenesis was comparable in all groups.Conclusions: The authors' results suggest a major role of ␣ 2 -adrenoceptors, especially the ␣ 2A subtype, in the mediation of thermoregulatory effects caused by meperidine in mice.