Stimulus properties of opioids with mixed agonist and antagonist activity

The discriminative stimulus properties of opioids with mixed agonist and antagonist activity are heterogeneous in contrast to the relative uniformity of the stimulus properties of classical morphinelike agonists. Patterns of stimulus generalization to mixed agonist-antagonists are critically dependent on factors such as the particular drug used for training, dose of the training drug, and species of the experimental subject. Opioids can be divided into three broad categories on the basis of their patterns of stimulus generalization in rats and squirrel monkeys trained to discriminate saline from morphine, cyclazocine, or phenyclidine (PCP), and these categories predict the ease with which their stimulus effects can be blocked by nalozone or naltrexone. 1) Opioids that are generalized completely to morphine; stimulus effects are easily antagonized. 2) Opioids that are generalized completely to cyclazocine; stimulus effects are antagonized with difficulty. 3) Opioids that are generalized completely to cyclazocine and PCP; stimulus effects not antagonized. The diversity of the stimulus properties of opioids is consistent with evidence that multiple populations of receptors subserve the actions of morphinelike agonists and agonist-antagonists. However, the stimulus effects of opioids in group 3 appear to be mediated by the same neuronal substrates that are acted on by PCP rather than by neuronal sites traditionally associated with the activity of opioids.