Three rhesus monkeys discriminated between 0.178 mg/kg of nalbuphine and saline while responding under a fixed-ratio 5 schedule of stimulus-shock termination. Nalbuphine produced dose-related increases in drug-lever responding with > or = 90% of responses occurring on the drug lever at doses larger than 0.1 mg/kg. The duration of action of the discriminative stimulus effects of nalbuphine was less than 5.25 hr. Rank order potency of compounds that substituted for the nalbuphine discriminative stimulus (i.e., > or = 90% responding on the nalbuphine lever) in all three subjects was fentanyl > butorphanol > methadone > morphine. Compounds that did not substitute completely in all monkeys included the kappa agonists ethylketocyclazocine, enadoline, spiradoline and U-50,488 and the nonopioids cocaine, d-amphetamine, clonidine, ketamine and phencyclidine. Naltrexone antagonized the discriminative stimulus effects of nalbuphine, shifting the nalbuphine dose-effect curve in a manner that was consistent with mu receptor mediation. Results from the current study demonstrate that, in rhesus monkeys, the discriminative stimulus effects of nalbuphine are mediated by mu opioid receptors. Although there is evidence suggesting that nalbuphine has kappa agonist effects (e.g., subjective effects in humans), results from several studies, including the current study, strongly suggest that in rhesus monkeys nalbuphine does not exert agonist actions at kappa receptors. Moreover, these data indicate that differences in behavioral effects between nalbuphine and prototypic mu opioids (e.g., morphine) probably result from differences in activity (e.g., efficacy) at mu receptors rather than any kappa agonist actions of nalbuphine.