Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Lower Saxony, Germany.
Anesthesiology. 2012 Jun;116(6):1335-46. doi: 10.1097/ALN.0b013e3182557917.
Opioids induce analgesia mainly by inhibiting synaptic transmission via G protein-coupled opioid receptors. In addition to analgesia, buprenorphine induces a pronounced antihyperalgesia and is an effective adjuvant to local anesthetics. These properties only partially apply to other opioids, and thus targets other than opioid receptors are likely to be employed. Here we asked if buprenorphine inhibits voltage-gated Na(+) channels.
Na(+) currents were examined by whole cell patch clamp recordings on different recombinant Na(+) channel α-subunits. The effect of buprenorphine on unmyelinated mouse C-fibers was examined with the skin-nerve preparation. Data are presented as mean ± SEM.
Buprenorphine induced a concentration-dependent tonic (IC(50) 33 ± 2 μM) and use-dependent block of endogenous Na(+) channels in ND7/23 cells. This block was state-dependent and displayed slow on and off characteristics. The effect of buprenorphine was reduced on local anesthetic insensitive Nav1.4-mutant constructs and was more pronounced on the inactivation-deficient Nav1.4-WCW mutant. Neuronal (Nav1.3, Nav1.7, and Nav1.8), cardiac (Nav1.5), and skeletal muscle (Nav1.4) α-subunits displayed small differences in tonic block, but similar degrees of use-dependent block. According to our patch clamp data, buprenorphine blocked electrically evoked action potentials in C-fiber nerve terminals. Buprenorphine was more potent than other opioids, including morphine (IC(50) 378 ± 20 μM), fentanyl (IC(50) 95 ± 5 μM), sufentanil (IC(50) 111 ± 6 μM), remifenatil (IC(50) 612 ± 17 μM), and tramadol (IC(50) 194 ± 9 μM).
Buprenorphine is a potent local anesthetic and blocks voltage-gated Na(+) channels via the local anesthetic binding site. This property is likely to be relevant when buprenorphine is used for pain treatment and for local anesthesia.
阿片类药物主要通过与 G 蛋白偶联阿片受体结合抑制突触传递来产生镇痛作用。除了镇痛作用外，丁丙诺啡还能显著抑制痛觉过敏，是局部麻醉剂的有效辅助药物。这些特性在其他阿片类药物中仅部分适用，因此可能会用到除阿片受体以外的其他靶点。在这里，我们想知道丁丙诺啡是否会抑制电压门控钠 (Na+) 通道。
通过全细胞膜片钳记录在不同的重组 Na+通道 α 亚基上研究 Na+电流。用皮肤-神经标本研究丁丙诺啡对无髓鼠 C 纤维的影响。数据以平均值±标准误表示。
丁丙诺啡在 ND7/23 细胞中诱导浓度依赖性的持续（IC50 为 33±2 μM）和使用依赖性的内源性 Na+通道阻断。这种阻断是状态依赖性的，表现出缓慢的导通和失活特征。局部麻醉剂不敏感的 Nav1.4 突变体构建体上丁丙诺啡的作用减弱，失活缺陷的 Nav1.4-WCW 突变体上的作用更为明显。神经元（Nav1.3、Nav1.7 和 Nav1.8）、心脏（Nav1.5）和骨骼肌（Nav1.4）α 亚基在持续阻断方面差异较小，但使用依赖性阻断程度相似。根据我们的膜片钳数据，丁丙诺啡阻断了 C 纤维神经末梢的电诱发动作电位。丁丙诺啡比其他阿片类药物（包括吗啡 [IC50 为 378±20 μM]、芬太尼 [IC50 为 95±5 μM]、舒芬太尼 [IC50 为 111±6 μM]、雷米芬太尼 [IC50 为 612±17 μM] 和曲马多 [IC50 为 194±9 μM]）更有效。
丁丙诺啡是一种有效的局部麻醉剂，通过局部麻醉剂结合位点阻断电压门控 Na+通道。当丁丙诺啡用于疼痛治疗和局部麻醉时，这种特性可能很重要。
