Bräu M E, Branitzki P, Olschewski A, Vogel W, Hempelmann G
Department of Anesthesiology and Intensive Care Medicine, Justus-Liebig-University, Giessen, Germany.
Anesth Analg. 2000 Dec;91(6):1499-505. doi: 10.1097/00000539-200012000-00038.
Tetrodotoxin (TTX)-sensitive Na(+) channels in the peripheral nervous system are the major targets for local anesthetics. In the peripheral nociceptive system, a Na(+) channel subtype resistant to TTX and with distinct electrophysiological properties seems to be of importance for impulse generation and conduction. A current through TTX-resistant Na(+) channels displays slower activation and inactivation kinetics and has an increased activation threshold compared with TTX-sensitive Na(+) currents and may have different pharmacological properties. We studied the effects of stereoisomers of piperidine local anesthetics on neuronal TTX-resistant Na(+) currents recorded with the whole-cell configuration of the patch clamp method in enzymatically dissociated dorsal root ganglion neurons of adult rats. Stereoisomers of mepivacaine, ropivacaine, and bupivacaine reversibly inhibited TTX-resistant Na(+) currents in a concentration and use-dependent manner. All drugs accelerated time course of inactivation. Half-maximal blocking concentrations were determined from concentration-inhibition relationships. Potencies for tonic and for use-dependent block increased with rising lipid solubilities of the drugs. Stereoselective action was not observed. We conclude that block of TTX-resistant Na(+) currents may lead to blockade of TTX-resistant action potentials in nociceptive fibers and consequently may be responsible for pain suppression during local anesthesia.
外周神经系统中对河豚毒素（TTX）敏感的钠通道是局部麻醉药的主要作用靶点。在外周伤害性感受系统中，一种对TTX耐药且具有独特电生理特性的钠通道亚型似乎对冲动的产生和传导至关重要。与对TTX敏感的钠电流相比，通过对TTX耐药的钠通道的电流表现出较慢的激活和失活动力学，且激活阈值升高，并且可能具有不同的药理学特性。我们采用膜片钳全细胞记录模式，研究了哌啶类局部麻醉药的立体异构体对成年大鼠酶解背根神经节神经元中记录到的神经元对TTX耐药的钠电流的影响。甲哌卡因、罗哌卡因和布比卡因的立体异构体以浓度和使用依赖性方式可逆性抑制对TTX耐药的钠电流。所有药物均加速了失活的时间进程。从浓度-抑制关系中确定半数最大阻断浓度。药物的强直阻断和使用依赖性阻断效能随脂溶性增加而增强。未观察到立体选择性作用。我们得出结论，对TTX耐药的钠电流的阻断可能导致伤害性感受纤维中对TTX耐药的动作电位的阻断，因此可能是局部麻醉期间疼痛抑制的原因。
