大多數(shù)局部麻醉劑的問(wèn)題是,，它們的作用沒(méi)有針對(duì)性。它們的親油性使它們能進(jìn)入幾乎任何神經(jīng)元,，在那里,，它們會(huì)不加甄別地阻斷細(xì)胞膜中的鈉通道,。一種阻斷特定痛覺(jué)神經(jīng)元的這種活性而又不影響其他感覺(jué)或運(yùn)動(dòng)神經(jīng)元的方法，也許可用來(lái)創(chuàng)建一種目標(biāo)性更強(qiáng)的局部麻醉方法,，而這正是Binshtok等人在本期Nature上提出的一個(gè)觀點(diǎn),。他們報(bào)告說(shuō),，利多卡因（lidocaine）衍生物QX-314可以定向于痛覺(jué)神經(jīng)元。正常情況下，QX-314不能穿過(guò)細(xì)胞膜,。但通過(guò)允許它經(jīng)TRPV1通道（一種辣椒素受體）進(jìn)入細(xì)胞可保證其止痛特效,，這個(gè)通道在細(xì)胞中只在痛覺(jué)神經(jīng)元中表達(dá)。對(duì)大鼠同時(shí)施用QX-314和辣椒素,，可阻斷其機(jī)械感覺(jué)和對(duì)熱的感覺(jué),，誘發(fā)局部麻醉，同時(shí)不會(huì)出現(xiàn)“正常的”利多卡因麻醉可能造成的癱瘓現(xiàn)象,。
原始出處:
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: [email protected]).
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.
