Methamphetamine and morphine were approximately equipotent in producing analgesia in mice using the tail-flick assay. The ED50 for morphine analgesia was significantly reduced when 3.2 mg/kg of methamphetamine was given 5 or 60 min before morphine. Methamphetamine pretreatment increased the peak effect but did not alter the duration of morphine analgesia. Enhancement of morphine analgesia was apparent when methamphetamine was given up to 60 min before morphine and it did not coincide with analgesia produced by methamphetamine alone. Brain levels of morphine were found to be significantly higher in methamphetamine- compared to saline-pretreated mice, at times when enhanced analgesia was observed. Further studies showed that morphine brain levels were increased by methamphetamine pretreatment in an apparent dose-dependent manner. The analgesia observed at several morphine brain levels was compared in order to determine whether enhanced analgesia resulted from increased morphine brain levels. Methamphetamine administration 5 or 60 min before morphine shifted the log morphine brain level-response curves for morphine analgesia to the left and the morphine brain level at a given percent analgesia was significantly lower in methamphetamine- than in saline-pretreated mice. In addition, methamphetamine pretreatment enhanced methadone analgesia but had no effect on methadone brain levels.