Article Text

Download PDFPDF
Mechanisms Underlying Midazolam-Induced Peripheral Nerve Block and Neurotoxicity
  1. Eser Yilmaz, MS*,,
  2. Karen A. Hough, AS, CVT, RLAT*,,
  3. Gerald F. Gebhart, PhD*,,
  4. Brian A. Williams, MD, MBA*,, and
  5. Michael S. Gold, PhD*,
  1. *Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, PA
  2. Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA
  3. VA Pittsburgh Health System, Pittsburgh, PA
  1. Address correspondence to: Michael S. Gold, PhD, 3500 Terrace St, Room E1440 BST, Pittsburgh, PA 15139 (e-mail: msg22{at}


Background and Objectives The benzodiazepine midazolam has been reported to facilitate the actions of spinally administrated local anesthetics. Interestingly, despite the lack of convincing evidence for the presence of γ-aminobutyric acid type A (GABAA) receptors along peripheral nerve axons, midazolam also has been shown to have analgesic efficacy when applied alone to peripheral nerves.

These observations suggest midazolam-induced nerve block is due to another site of action. Furthermore, because of evidence indicating that midazolam has equal potency at the benzodiazepine site on the GABAA receptor and the 18-kd translocator protein (TSPO), it is possible that at least the nerve-blocking actions of midazolam are mediated by this alternative site of action.

Methods We used the benzodiazepine receptor antagonist flumazenil, and the TSPO antagonist PK11195, with midazolam on rat sciatic nerves and isolated sensory neurons to determine if either receptor mediates midazolam-induced nerve block and/or neurotoxicity.

Results Midazolam (300 μM)–induced block of nerve conduction was reversed by PK11195 (3 μM), but not flumazenil (30 μM). Midazolam-induced neurotoxicity was blocked by neither PK11195 nor flumazenil. Midazolam also causes the release of Ca2+ from internal stores in sensory neurons, and there was a small but significant attenuation of midazolam-induced neurotoxicity by the Ca2+ chelator, BAPTA. BAPTA (30 μM) significantly attenuated midazolam-induced nerve block.

Conclusions Our results indicate that processes underlying midazolam-induced nerve block and neurotoxicity are separable, and suggest that selective activation of TSPO may facilitate modality-selective nerve block while minimizing the potential for neurotoxicity.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • The authors declare no conflict of interest.

    This research is supported by the Department of Defense grant OR090012 to B.A.W., M.S.G., and G.F.G.