title: Mechanisms underlying midazolam-induced peripheral nerve block and neurotoxicity.
abstract: OBJECTIVE
  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 Ca from internal stores in sensory neurons, and there was a small but significant attenuation of midazolam-induced neurotoxicity by the Ca 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.
authors.affiliation: From the *Center for Pain Research and †Department of Anesthesiology, University of Pittsburgh School of Medicine; and ‡VA Pittsburgh Health System, Pittsburgh, PA.
authors.forename: Eser
authors.initials: E
authors.lastname: Yilmaz
authors.forename: Karen A
authors.initials: KA
authors.lastname: Hough
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Gebhart
authors.forename: Brian A
authors.initials: BA
authors.lastname: Williams
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gold
mesh_terms: D000200:Action Potentials; D000700:Analgesics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D065096:Calcium Chelating Agents / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002352:Carrier Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000494:pharmacology* / Q000633:toxicity; D009407:Nerve Block / Q000379:methods*; D009431:Neural Conduction / Q000187:drug effects*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D020426:Sciatic Neuropathy / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000700:Analgesics; D065096:Calcium Chelating Agents; D002352:Carrier Proteins; D007546:Isoquinolines; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; D005442:Flumazenil; D004533:Egtazic Acid; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D003975:Diazepam; D008874:Midazolam; C037850:PK 11195