Abstract
The mechanisms underlying benzodiazepine antagonism of opioid antinociception were studied using the tail flick test and the hot plate test in mice. Both single-dose and repeated diazepam treatment antagonized the antinociceptive effect of morphine. The specific benzodiazepine antagonist flumazenil completely reversed the antagonism between diazepam and morphine. Mid-thoracic spinalization also abolished the antagonism, indicating that the antagonism takes place at higher levels in the CNS. Neither diazepam nor midazolam showed any affinity for opioid mu or kappa receptors in membranes prepared from mouse forebrain. Taken together with the results of other studies of interactions between GABAergic drugs and opioids, the results indicate that a benzodiazepine receptor-mediated mechanism at higher levels in the CNS, possibly in the brainstem, blocks the effect of opioids on nociceptive transmission.
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