DISCRIMINATIVE STIMULUS EFFECTS OF NALBUPHINE IN RHESUS-MONKEYS

Three rhesus monkeys discriminated between 0.178 mg/kg of nalbuphine a nd saline while responding under a fixed-ratio 5 schedule of stimulus- shock termination. Nalbuphine produced dose-related increases in drug- lever responding with greater than or equal to 90% of responses occurr ing 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 t han 5.25 hr. Rank order potency of compounds that substituted for the nalbuphine discriminative stimulus (i.e., greater than or equal to 90% responding on the nalbuphine lever) in all three subjects was fentany l > butorphanol > methadone > morphine. Compounds that did not substit ute completely in all monkeys included the kappa agonists ethyl ketocy clazocine, enadoline, spiradoline and U-50,488 and the nonopioids coca ine, d-amphetamine, clonidine, ketamine and phencyclidine. Naltrexone antagonized the discriminative stimulus effects of nalbuphine, shiftin g the nalbuphine dose-effect curve in a manner that was consistent wit h mu receptor mediation. Results from the current study demonstrate th at, in rhesus monkeys, the discriminative stimulus effects of nalbuphi ne are mediated by mu opioid receptors. Although there is evidence sug gesting that nalbuphine has kappa agonist effects (e.g., subjective ef fects in humans), results from several studies, including the current study, strongly suggest that in rhesus monkeys nalbuphine does not exe rt agonist actions at kappa receptors. Moreover, these data indicate t hat differences in behavioral effects between nalbuphine and prototypi c mu opioids (e.g., morphine) probably result from differences in acti vity (e.g., efficacy) at mu receptors rather than any kappa agonist ac tions of nalbuphine.