A dose of 40 mg/kg of meperidine (pethidine) caused a marked lowering of rectal temperature in restrained female rats at room temperature (22 degrees C). This decrease was not antagonized by injection of 1 mg/kg of naloxone, whereas hypothermia of equal magnitude induced by 20 mg/kg of morphine was reversed by 1 mg/kg of naloxone. Pretreatment with the serotonin reuptake blocker, fluoxetine (10 mg/kg), or a non-hypothermic dose of meperidine (20 mg/kg) significantly potentiated the hypothermia induced by 100 mg/kg of l-5-hydroxytryptophan. The hypothermic effect of 40 mg/kg of meperidine was significantly greater than that of 10 mg/kg of fluoxetine. Finally, 40 mg/kg of meperidine produced a significantly greater hypothermic effect in restrained rats than in unrestrained rats. The results indicate that the hypothermic effect of meperidine is not a result of an opioid action, and that although it may be mediated through serotonergic systems, inhibition of serotonin reuptake is probably not the primary mechanism.