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Anesth Analg 2001;93:354-358
© 2001 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Effects of Benzodiazepines on Human Opioid Receptor Binding and Function

Richard F. Cox, PhD*, and Mark A. Collins{dagger}

Departments of *Receptor Biochemistry and {dagger}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 {kappa} and {delta} receptors, but not µ receptors, whereas flumazenil was inactive. These benzodiazepines also stimulated 35S-GTP{gamma}S 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 µ 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 [3H]-diprenorphine—an opiate radioligand from {kappa} receptors. In an in vitrofunctional 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.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press
Copyright © 2001 by the International Anesthesia Research Society.