Antinociceptive and respiratory effects of nalbuphine and other opioids were studied in rhesus monkeys. In a thermal, tail withdrawal assay, the kappa agonist enadoline and the mu agonists alfentanil and fentanyl produced maximum antinociceptive effects in all subjects and over a wide range of temperatures, whereas nalbuphine produced antinociceptive effects in only some subjects and only when the water temperature was < or = 50 degrees C. Naltrexone antagonized the antinociceptive effects of nalbuphine, alfentanil and enadoline; however, the magnitude of antagonism was not equal among agonists. In subjects that did not show an antinociceptive response to nalbuphine, nalbuphine (3.2-10.0 mg/kg) antagonized the antinociceptive effects of fentanyl but not enadoline. The irreversible opioid antagonist clocinnamox produced a parallel shift to the right in the nalbuphine dose-effect curve 1 hr after administration and decreased the maximum effect produced by nalbuphine 24 and 48 hr after administration. Nalbuphine had modest respiratory-depressant effects in monkeys breathing air and attenuated hyperventilation produced by 5% CO2. In contrast, alfentanil had marked respiratory-depressant effects in monkeys breathing air or 5% CO2 in air and these effects were antagonized by nalbuphine. Taken together, these results suggest nalbuphine has low efficacy at mu opioid receptors; however, quantitative differences between alfentanil and nalbuphine indicate a second (non-enadoline sensitive) receptor might also be important for the antinociceptive effects of nalbuphine.