OPIOID ANTAGONISTS - INDIRECT ANTAGONISM OF MORPHINE ANALGESIA BY SPINAL DYNORPHIN-A

Naloxone and norbinaltorphimine when given ICV to mice can antagonize IT morphine-induced analgesia indirectly by releasing spinal dynorphin A(1-17) (Dyn A). Dyn A produces an antianalgesic action against IT mo rphine. In the present study, drugs with varying amounts of opioid ant agonist to agonist action (nalbuphine, levallorphan, naltrexone, and n altrindole) were given ICV to determine whether they antagonized IT mo rphine-induced inhibition of the tail-flick response as an indication of spinal Dyn A release. Additional pharmacological tests were used as criteria for Dyn A release: a) Small doses of the opioid antagonists naloxone and norbinaltorphimine administered IT inhibited the antagoni stic action; b) dynorphin antiserum given IT blocked the action of Dyn A; c) desensitization to the effect of Dyn A was produced by 3-h pret reatment with morphine, 10 mg/kg SC, or by pretreatment with the agent s themselves. When given ICV, nalbuphine, levallorphan, and naltrexone released Dyn A in the spinal cord to produce an antianalgesic effect. Naltrindole, a delta-receptor antagonist, did not release Dyn A. Dyn A release did not appear to involve delta-receptors. Thus, a number of opioid antagonists inhibit the analgesic action of opioid agonists in directly through Dyn A release.