Limitations on the antagonistic actions of opioid antagonists.

This paper reviews factors that may limit or modify the behavioral actions of opioid antagonists under schedules of operant behavior in laboratory animals. The surmountable antagonism of opioid agonists by the antagonists is limited by the characteristics of both. Decreases in schedule-controlled responding produced by the prototypic agonist morphine are reversed by appropriate doses of antagonists such as naloxone, naltrexone, nalorphine, and cyclazocine. The ability of each antagonist to reverse the behavioral effects of morphine is limited, however, by the doses of agonist and antagonist used. The efficacies of high doses of antagonists are limited by the drugs' direct rate-decreasing actions. There also are differences among agonists in their sensitivity to antagonism. Naloxone and naltrexone are more potent as antagonists of morphine than of cyclazocine under certain conditions. Effective antagonism of the behavioural effects of opioid agonists appears to require entry into the central nervous system, indicated by the ineffectiveness of quaternary naltrexone, a peripherally acting opioid antagonist. The direct behavioral actions of the antagonists also can be modified by pharmacological conditions. The potency of antagonists in decreasing response rates is increased during chronic morphine administration. In addition, supersensitivity to the direct rate-decreasing actions of naloxone and naltrexone may develop after chronic antagonists administration. Such changes in the potency of antagonists also may modify the interactions of agonists and their antagonists.