DYNORPHIN A(1-17) MEDIATES MIDAZOLAM ANTAGONISM OF MORPHINE ANTINOCICEPTION IN MICE

Studies have shown that midazolam acts in the brain to antagonize the antinociception produced by morphine. The purpose of this study was to determine if spinal dynorphin A(1-17) (Dyn) was involved in the antagonistic effects of midazolam. A number of drugs when administered intracerebroventricularly (ICV) to mice release Dyn in the spinal cord to antagonize morphine-induced antinociception. In the present study using the mouse tail-flick test, midazolam administered ICV produced a dose related reduction of the antinociception induced by morphine given intrathecally (IT). The antagonistic action of midazolam against morphine-induced antinociception involved the release of Dyn in the spinal cord, as evidenced by the following results. 1) Administration of naloxone, norbinaltorphimine and dynorphin antiserum, IT, eliminated the antagonistic effect of midazolam. given ICV, against morphine. Treatment with these opioid antagonists and dynorphin antiserum is known to inhibit the action of spinally released Dyn. 2) Production of desensitization to the effect of spinal Dyn by pretreating with morphine, 10 mg/kg subcutaneously 3 h before the tail-flick test, abolished the antagonistic action of midazolam given ICV. A 3-h pretreatment with midazolam, ICV, also produced desensitization to the antagonistic action of Dyn given IT. 3) Elimination of the Dyn component of action of midazolam by administration of naloxone, nor-binaltorphimine and dynorphin antiserum, IT, uncovered slight antinociceptive activity of midazolam, given ICV. Coadministration of flumazenil (a benzodiazepine antagonist), bicuculline (a GABA antagonist) and picrotoxin (a chloride ion channel blocker) inhibited the midazolam effect. Thus, activation of the supraspinal GABA/benzodiazepine receptor complex by midazolam appeared to be involved in the antagonistic action of midazolam and the release of spinal Dyn.