The effect of chronic opioid antagonist treatment on the analgesic potency of six opioid agonists was compared to changes in opioid receptor density and the selectivity of each agonist for mu (DAMGO), delta (DPDPE) and kappa (U69,593) opioid receptors. Mice were implanted SC with a 15-mg naltrexone or placebo pellet for 8 days. The pellets were removed and 24 h later, mice were sacrificed and binding studies were conducted, or mice were tested in analgesia (tail-flick) dose-response studies. All six analgesics acted as full agonists for both placebo and naltrexone-treated mice. Naltrexone increased the analgesic potency of methadone, etorphine, fentanyl, meperidine, and oxycodone by 1.9-3.2-fold. The analgesic potency of propoxyphene was not increased significantly (1.3-fold). In saturation binding studies in brain homogenate, naltrexone increased the Bmax of mu, delta, and kappa opioid receptors by 86, 43, and 33%, respectively, without altering Kd. Competition binding studies for each receptor type were conducted in brains from untreated mice, and KIs were determined for each agonist. All agonists had greatest selectivity toward mu compared with delta and kappa receptors. There did not appear to be an obvious relationship between receptor selectivity and the magnitude of supersensitivity. These studies indicate that supersensitivity occurs for a broad range of opioid analgesics following chronic opioid antagonist treatment in the mouse. However, the selectivity of these agonists for mu, delta, and kappa receptors does not appear to correlate with differences in supersensitivity.