The effects of benzodiazepines on human opioid receptor binding and function.

UNLABELLED We performed in vitro studies to investigate the potential interaction of benzodiazepines with cloned human opioid receptor subtypes. Midazolam, chlordiazepoxide, and diazepam directly displaced [(3)H]-diprenorphine binding from kappa and delta receptors, but not mu receptors, whereas flumazenil was inactive. These benzodiazepines also stimulated (35)S-GTPgammaS binding in membranes containing human kappa receptors, and the effect of midazolam was prevented by a selective kappa antagonist. Midazolam was also weakly active at delta-receptor activation, whereas all three were inactive at mu receptors. The results suggest that the analgesic efficacy reported for intrathecal benzodiazepines may be attributed, in part, to direct interaction with kappa-opioid receptors. IMPLICATIONS Several human and animal studies have shown analgesic effects of benzodiazepines after spinal injection. Our results show that large concentrations of midazolam, chlordiazepoxide, and diazepam displace the binding of [(3)H]-diprenorphine-an opiate radioligand from kappa receptors. In an in vitro functional assay, midazolam is a weak agonist at the delta-opioid receptor, whereas all three benzodiazepines are kappa-opioid agonists. These findings may partially explain the mechanism of benzodiazepine-induced spinal analgesia.