Assessment of the agonist and antagonist properties of nalorphine

It has previously been reported that subjects trained to discriminate either the mu antagonist naloxone or mu agonist morphine from its vehicle generalized stimulus control to nalorphine, effects presumably due to nalorphine's intermediate efficacy at the mu opiate receptor subtype. In an attempt to assess the efficacy of nalorphine relative to naloxone (none) and morphine (high), subjects were trained within the taste aversion baseline of drug discrimination learning to respond differentially to naloxone and morphine in a two-drug discrimination procedure. Following the acquisition of the discrimination, nalorphine, as well as the mu agonists methadone and buprenorphine, produced morphine-appropriate responding, while the mu antagonists naltrexone and diprenorphine produced responding appropriate for naloxone. These data suggest that when the relative efficacy of nalorphine is examined, nalorphine lies closer to morphine than naloxone along the continuum of relative efficacy (Experiment 1). Given that in Experiment 1 nalorphine substituted for morphine-trained subjects, but not to naloxone-trained subjects, it was expected that when subjects were trained to discriminate nalorphine from vehicle, nalorphine would generalize this control to morphine but not to naloxone or naltrexone (Experiment 2). Following acquisition of the discrimination, nalorphine stimulus control generalized completely to morphine in five of six subjects, while with the exception of a single subject, naltrexone and naloxone failed to do so. The broad-based opiate antagonist diprenorphine also engendered nalorphine-appropriate responding in all subjects. That nalorphine generalized to morphine but not to naloxone or naltrexone, is consistent with the expectation that nalorphine is a partial agonist at the mu receptor with efficacy closer to morphine than to naloxone. That diprenorphine substituted for nalorphine suggests that diprenorphine, like nalorphine, possesses partial agonist activity. From the present studies, it is suggested that opiates lie on a continuum of efficacy ranging from no efficacy to maximum efficacy and that they can be rank ordered in terms of their relative intrinsic effects: $\rm naloxone\le naltrexone<diprenorphine<nalorphine< buprenorphine\le methadone\le morphine.$ Given that opiates are known to act at multiple receptor sites, this analysis of the continuum of relative efficacy may not be limited to a single site (e.g., mu), but may be applied to other opiate receptor sites (e.g., kappa and delta) as well.Source: Dissertation Abstracts International, Volume: 56-03, Section: B, page: 1739.Advisors: Anthony Riley.Ph.D. American University 1994.Englis