Opioid antagonists: indirect antagonism of morphine analgesia by spinal dynorphin A

Naloxone and norbinaltorphimine when given ICV 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 morphine. In the present study, drugs with varying amounts of opioid antagonist to agonist action (nalbuphine, levallorphan, naltrexone, and naltrindole) were given ICV to determine whether they antagonized IT morphine-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 antagonistic 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 pretreatment with morphine, 10 mg/kg SC, or by pretreatment with the agents themselves. When given ICV, nalbuphine, levallorphan, and naltrexone released Dyn A in the spinal cord to produce an antianalgesic effect. Naltrindole, a δ-receptor antagonist, did not release Dyn A. Dyn A release did not appear to involve δ-receptors. Thus, a number of opioid antagonists inhibit the analgesic action of opioid agonists indirectly through Dyn A release.