Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers
Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers
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DOI：
10.1038/nature06191
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发表时间：
2007-10-04
期刊：
影响因子：
64.8
通讯作者：
Woolf, Clifford J.
中科院分区：
文献类型：
--
作者：
Binshtok, Alexander M.;Bean, Bruce P.;Woolf, Clifford J.
临床上使用的大多数局部麻醉剂都是相对疏水的分子，它们通过扩散到或穿过细胞膜来进入钠通道上的阻断位点 (1)。这些麻醉剂会阻断钠通道，从而阻断所有神经元的兴奋性，而不仅仅是感觉神经元。我们通过有毒热敏感 TRPV1 通道的孔引入带电的膜非渗透性利多卡因衍生物 QX-314，测试了选择性阻断初级感觉伤害感受器（痛觉）神经元兴奋性的可能性。在这里，我们表明，通过应用 TRPV1 激动剂，带电钠通道阻滞剂可以靶向伤害感受器，产生疼痛特异性的局部麻醉。单独使用时，外用 QX-314 对小感觉神经元中钠通道的活性没有影响，但当与 TRPV1 激动剂辣椒素一起使用时，QX-314 会阻断钠通道并抑制兴奋性。共同应用 QX-314 和辣椒素的抑制仅限于表达 TRPV1 的神经元。将 QX-314 与辣椒素一起注射到大鼠后爪中，会产生机械和热伤害感受阈值的持久（超过 2 小时）增加。在坐骨神经附近局部注射 QX-314 和辣椒素也可以观察到疼痛敏感性的长期下降；然而，与利多卡因的效果相反，同时使用 QX-314 和辣椒素并不伴随运动或触觉缺陷。
Most local anaesthetics used clinically are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane(1). These anaesthetics block sodium channels and thereby the excitability of all neurons, not just sensory neurons. We tested the possibility of selectively blocking the excitability of primary sensory nociceptor (pain-sensing) neurons by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel. Here we show that charged sodium-channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anaesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability. Inhibition by co-applied QX-314 and capsaicin was restricted to neurons expressing TRPV1. Injection of QX-314 together with capsaicin into rat hindpaws produced a long-lasting (more than 2 h) increase in mechanical and thermal nociceptive thresholds. Long-lasting decreases in pain sensitivity were also seen with regional injection of QX-314 and capsaicin near the sciatic nerve; however, in contrast to the effect of lidocaine, the application of QX-314 and capsaicin together was not accompanied by motor or tactile deficits.