Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents.
Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents.
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DOI：
10.1097/aln.0b013e3181a915e7
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发表时间：
2009-07
期刊：
影响因子：
8.8
通讯作者：
Woolf CJ
中科院分区：
文献类型：
--
作者：
Binshtok AM;Gerner P;Oh SB;Puopolo M;Suzuki S;Roberson DP;Herbert T;Wang CF;Kim D;Chung G;Mitani AA;Wang GK;Bean BP;Woolf CJ
当与辣椒素（一种瞬时受体电位香草素1（TRPV 1）通道激动剂）共同给药时，永久带电的利多卡因衍生物QX-314进入伤害感受器，从而产生伤害感受性选择性局部麻醉。然而，在建立QX-314介导的阻滞之前由辣椒素诱发的疼痛将限制临床应用。由于TRPV 1通道也被利多卡因激活，作者测试了利多卡因是否可以替代辣椒素通过TRPV 1通道将QX-314引入伤害感受器并产生选择性镇痛。在大鼠和小鼠的坐骨神经附近皮下注射单独的利多卡因（0.5% [17.5 mm]、1% [35 mm]和2% [70 mm]）、单独的QX-314（0.2% [5.8 mm]）以及两者的组合。机械和热反应性进行了测量，因为是运动阻滞。与利多卡因单独给药相比，0.2%QX-314与利多卡因联合给药延长了伤害性阻滞，在TRPV 1基因敲除小鼠中这种作用减弱。当足底内或神经束膜注射时，单独的0.2%QX-314没有作用，并且其仅对皮肤干肌反射产生弱的短暂抑制。在坐骨神经周围注射QX-314产生的差异性伤害性阻滞比短暂运动阻滞长得多，持续2 h（1%利多卡因）至9 h（2%利多卡因）。利多卡因、QX-314和辣椒素的三重应用进一步增加了差异性阻滞的持续时间。利多卡因及其季铵衍生物QX-314的共同应用产生了持久的，主要是伤害感受器选择性阻滞，可能是通过促进QX-314通过TRPV 1通道进入。通过使用利多卡因代替辣椒素将QX-314递送到伤害感受器中产生持续的区域镇痛而没有伤害性行为。
Nociceptive-selective local anesthesia is produced by entry of the permanently charged lidocaine-derivative QX-314 into nociceptors when coadministered with capsaicin, a transient receptor potential vanilloid 1 (TRPV1) channel agonist. However, the pain evoked by capsaicin before establishment of the QX-314–mediated block would limit clinical utility. Because TRPV1 channels are also activated by lidocaine, the authors tested whether lidocaine can substitute for capsaicin to introduce QX-314 into nociceptors through TRPV1 channels and produce selective analgesia. Lidocaine (0.5% [17.5 mm], 1% [35 mm], and 2% [70 mm]) alone, QX-314 (0.2% [5.8 mm]) alone, and a combination of the two were injected subcutaneously and adjacent to the sciatic nerve in rats and mice. Mechanical and thermal responsiveness were measured, as was motor block. Coapplication of 0.2% QX-314 with lidocaine prolonged the nociceptive block relative to lidocaine alone, an effect attenuated in TRPV1 knockout mice. The 0.2% QX-314 alone had no effect when injected intraplantary or perineurally, and it produced only weak short-lasting inhibition of the cutaneous trunci muscle reflex. Perisciatic nerve injection of lidocaine with QX-314 produced a differential nociceptive block much longer than the transient motor block, lasting 2 h (for 1% lidocaine) to 9 h (2% lidocaine). Triple application of lidocaine, QX-314, and capsaicin further increased the duration of the differential block. Coapplication of lidocaine and its quaternary derivative QX-314 produces a long-lasting, predominantly nociceptor-selective block, likely by facilitating QX-314 entry through TRPV1 channels. Delivery of QX-314 into nociceptors by using lidocaine instead of capsaicin produces sustained regional analgesia without nocifensive behavior.