大多数局部麻醉剂的问题是，它们的作用没有针对性。它们的亲油性使它们能进入几乎任何神经元，在那里，它们会不加甄别地阻断细胞膜中的钠通道。一种阻断特定痛觉神经元的这种活性而又不影响其他感觉或运动神经元的方法，也许可用来创建一种目标性更强的局部麻醉方法，而这正是Binshtok等人在本期Nature上提出的一个观点。他们报告说，利多卡因（lidocaine）衍生物QX-314可以定向于痛觉神经元。正常情况下，QX-314不能穿过细胞膜。但通过允许它经TRPV1通道（一种辣椒素受体）进入细胞可保证其止痛特效，这个通道在细胞中只在痛觉神经元中表达。对大鼠同时施用QX-314和辣椒素，可阻断其机械感觉和对热的感觉，诱发局部麻醉，同时不会出现“正常的”利多卡因麻醉可能造成的瘫痪现象。
原始出处:
Nature 449, 607-610 (4 October 2007) | doi:10.1038/nature06191; Received 21 June 2007; Accepted 28 August 2007
Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers
Alexander M. Binshtok1, Bruce P. Bean2 & Clifford J. Woolf1
Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA
Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA
Correspondence to: Bruce P. Bean2 Correspondence and requests for materials should be addressed to B.P.B. (Email: bruce_bean@hms.harvard.edu).
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 membrane1. 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.
