From the *Center for Pain Research and †Department of Anesthesiology, University of Pittsburgh School of Medicine; and ‡VA Pittsburgh Health System, Pittsburgh, PA.
Reg Anesth Pain Med. 2014 Nov-Dec;39(6):525-33. doi: 10.1097/AAP.0000000000000176.
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.
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.
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.
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.
苯二氮䓬类药物咪达唑仑已被报道可促进椎管内局部麻醉药的作用。有趣的是，尽管外周神经轴突上缺乏γ-氨基丁酸 A 型（GABAA）受体存在的令人信服的证据，但咪达唑仑单独应用于外周神经时也显示出镇痛效果。这些观察结果表明，咪达唑仑诱导的神经阻滞是由于另一种作用部位。此外，由于有证据表明咪达唑仑在 GABAA 受体的苯二氮䓬结合部位和 18kD 转位蛋白（TSPO）上具有同等效力，因此至少咪达唑仑的神经阻滞作用是通过这种替代作用部位介导的。
我们使用苯二氮䓬受体拮抗剂氟马西尼和 TSPO 拮抗剂 PK11195 与咪达唑仑一起作用于大鼠坐骨神经和分离的感觉神经元，以确定是否有任何受体介导咪达唑仑诱导的神经阻滞和/或神经毒性。
咪达唑仑（300μM）诱导的神经传导阻滞被 PK11195（3μM）逆转，但氟马西尼（30μM）不能逆转。PK11195 和氟马西尼均不能阻断咪达唑仑诱导的神经毒性。咪达唑仑还导致感觉神经元内钙库释放钙，钙螯合剂 BAPTA 可轻微但显著减弱咪达唑仑诱导的神经毒性。BAPTA（30μM）显著减弱咪达唑仑诱导的神经阻滞。
我们的结果表明，咪达唑仑诱导的神经阻滞和神经毒性的机制是可分离的，并表明 TSPO 的选择性激活可能促进模式选择性神经阻滞，同时最大限度地减少神经毒性的可能性。
