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ANESTHETIC PHARMACOLOGY

The Effects of Benzodiazepines on Human Opioid Receptor Binding and Function

Richard F. Cox, PhD^*, and Mark A. Collins

Departments of *Receptor Biochemistry and Molecular Pharmacology, GlaxoSmithKline, Research Triangle Park, North Carolina

Address correspondence and reprint requests to Richard F. Cox, PhD, Systems Research, GlaxoSmithKline, Research Triangle Park, NC 27709. Address e-mail to rc7694{at}glaxowellcome.com

We performed in vitrostudies to investigate the potential interaction of benzodiazepines with cloned human opioid receptor subtypes. Midazolam, chlordiazepoxide, and diazepam directly displaced [³H]-diprenorphine binding from and receptors, but not µ receptors, whereas flumazenil was inactive. These benzodiazepines also stimulated ³⁵S-GTPS binding in membranes containing human receptors, and the effect of midazolam was prevented by a selective antagonist. Midazolam was also weakly active at -receptor activation, whereas all three were inactive at µ receptors. The results suggest that the analgesic efficacy reported for intrathecal benzodiazepines may be attributed, in part, to direct interaction with -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 [³H]-diprenorphine—an opiate radioligand from receptors. In an in vitrofunctional assay, midazolam is a weak agonist at the -opioid receptor, whereas all three benzodiazepines are -opioid agonists. These findings may partially explain the mechanism of benzodiazepine-induced spinal analgesia.

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