Scholz A, Kuboyama N, Hempelmann G, Vogel W
Physiologisches Institut, Justus-Liebig-Universität Giessen, D-35392 Giessen, Germany.
J Neurophysiol. 1998 Apr;79(4):1746-54. doi: 10.1152/jn.1998.79.4.1746.
Mechanisms of blockade of tetrodotoxin-resistant (TTXr) Na+ channels by local anesthetics in comparison with the sensitivity of tetrodotoxin-sensitive (TTXs) Na+ channels were studied by means of the patch-clamp technique in neurons of dorsal root ganglions (DRG) of rat. Half-maximum inhibitory concentration (IC50) for the tonic block of TTXr Na+ currents by lidocaine was 210 micromol/l, whereas TTXs Na+ currents showed five times lower IC50 of 42 micromol/l. Bupivacaine blocked TTXr and TTXs Na+ currents more potently with IC50 of 32 and 13 micromol/l, respectively. In the inactivated state, TTXr Na+ channel block by lidocaine showed higher sensitivities (IC50 = 60 micromol/l) than in the resting state underlying tonic blockade. The time constant tau1 of recovery of TTXr Na+ channels from inactivation at -80 mV was slowed from 2 to 5 ms after addition of 10 micromol/l bupivacaine, whereas the tau2 value of approximately 500 ms remained unchanged. The use-dependent block of TTXr Na+ channels led to a progressive reduction of current amplitudes with increasing frequency of stimulation, which was </=53% block at 20 Hz in 10 micromol/l bupivacaine and 81% in 100 micromol lidocaine. The functional importance of the use-dependent block was confirmed in current-clamp experiments where 30 micromol/l of lidocaine or bupivacaine did not suppress the single action potential but clearly reduced the firing frequency of action potentials again with stronger potency of bupivacaine. Because it was found that TTXr Na+ channels predominantly occur in smaller sensory neurons, their blockade might underlie the suppression of the sensation of pain. Different sensitivities and varying proportions of TTXr and TTXs Na+ channels could explain the known differential block in spinal anesthesia. We suggest that the frequency reduction at low local anesthetic concentrations may explain the phenomenon of paresthesia where sensory information are suppressed gradually during spinal anesthesia.
采用膜片钳技术，在大鼠背根神经节（DRG）神经元中研究了局部麻醉药对河豚毒素抗性（TTXr）钠通道的阻断机制，并与河豚毒素敏感性（TTXs）钠通道的敏感性进行了比较。利多卡因对TTXr钠电流的强直阻断的半数最大抑制浓度（IC50）为210微摩尔/升，而TTXs钠电流的IC50低五倍，为42微摩尔/升。布比卡因对TTXr和TTXs钠电流的阻断作用更强，IC50分别为32和13微摩尔/升。在失活状态下，利多卡因对TTXr钠通道的阻断表现出比强直阻断的静息状态更高的敏感性（IC50 = 60微摩尔/升）。在添加10微摩尔/升布比卡因后，TTXr钠通道从-80 mV失活状态恢复的时间常数tau1从2毫秒减慢至5毫秒，而约500毫秒的tau2值保持不变。TTXr钠通道的使用依赖性阻断导致随着刺激频率增加电流幅度逐渐降低，在10微摩尔/升布比卡因中20 Hz时阻断率≤53%，在100微摩尔利多卡因中为81%。在电流钳实验中证实了使用依赖性阻断的功能重要性，其中30微摩尔/升的利多卡因或布比卡因不抑制单个动作电位，但明显降低动作电位的发放频率，布比卡因的作用更强。因为发现TTXr钠通道主要存在于较小的感觉神经元中，它们的阻断可能是疼痛感觉抑制的基础。TTXr和TTXs钠通道的不同敏感性和不同比例可以解释脊髓麻醉中已知的差异阻断。我们认为，低局部麻醉药浓度下的频率降低可能解释了感觉异常现象，即在脊髓麻醉期间感觉信息逐渐被抑制。
