The effect of MK-801 on morphine-induced analgesia, tolerance and opioid binding sites was examined in mice. In analgesia studies, mice received either naloxone or MK-801. Controls were injected with saline. Mice were then injected with morphine 10 or 30 min following naloxone or MK-801, respectively, and tested for analgesia (tail flick assay) 45 min later. Pretreatment with naloxone or MK-801 blocked morphine-induced analgesia. In tolerance studies, mice were pretreated with either saline or MK-801. Thirty minutes later, mice were injected with either saline or morphine (acutely or chronically) and tested for analgesia 24 h later. Pretreatment with MK-801 partially or completely blocked the development of acute and chronic tolerance, respectively. In binding studies, MK-801 displaced [3H]naloxone poorly compared to naloxone or morphine. Together, these data suggest a role for NMDA receptors in morphine-induced analgesia and tolerance. The poor inhibition of the [3H]naloxone binding sites by MK-801 supports the possibility that MK-801 might not act directly on the opioid receptors, but rather, inhibits morphine-induced analgesia and tolerance by some other mechanisms.