Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade.
Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade.
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DOI：
10.1038/nm.3978
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发表时间：
2015-11
期刊：
影响因子：
82.9
通讯作者：
Ji RR
中科院分区：
文献类型：
--
作者：
Xu ZZ;Kim YH;Bang S;Zhang Y;Berta T;Wang F;Oh SB;Ji RR
由正常无害的低阈值机械刺激引起的机械性异常性疼痛代表了神经性疼痛的主要特征。阻断或消融高阈值小直径无髓C纤维对机械性异常性疼痛的影响有限。虽然大的有髓A纤维，特别是Aβ纤维，以前已经涉及机械异常性疼痛，但仍然缺乏A纤维选择性药理学阻断剂。在这里，我们报告了一种新的方法，有针对性地沉默神经病理性疼痛的A-纤维。我们发现Toll样受体5（TLR 5）与神经丝200在背根神经节（DRG）的大直径A纤维神经元中共表达。TLR 5与其配体鞭毛蛋白的激活导致膜不可渗透的利多卡因衍生物QX-314进入神经元，导致主要在小鼠DRG的A纤维神经元中的钠电流的TLR 5依赖性阻断。鞭毛蛋白和QX-314（鞭毛蛋白/QX-314）的足底共同应用剂量依赖性地抑制化疗后的机械异常性疼痛、神经损伤和糖尿病性神经病变，但这种阻断在Tlr 5缺陷小鼠中被废除。体内电生理学证明，鞭毛蛋白/QX-314共同应用选择性地抑制幼稚和化疗处理的小鼠中的Aβ纤维传导。TLR 5介导的Aβ阻断剂（而非辣椒素介导的C纤维阻断剂）也可减轻化疗诱导的持续性疼痛，而不损害运动功能。最后，鞭毛蛋白/QX-314共同应用抑制大直径人DRG神经元中的钠电流。因此，我们的研究结果为靶向沉默Aβ纤维和神经病理性疼痛治疗提供了新的工具。
Mechanical allodynia, induced by normally innocuous low-threshold mechanical stimulation, represents a cardinal feature of neuropathic pain. Blockade or ablation of high-threshold small-diameter unmyelinated C-fibers has limited effects on mechanical allodynia. While large myelinated A-fibers, in particular Aβ-fibers, have previously been implicated in mechanical allodynia, an A-fiber-selective pharmacological blocker is still lacking. Here we report a new method for targeted silencing of A-fibers in neuropathic pain. We found that Toll-like receptor 5 (TLR5) is co-expressed with neurofilament-200 in large-diameter A-fiber neurons in the dorsal root ganglion (DRG). Activation of TLR5 with its ligand flagellin results in neuronal entry of the membrane impermeable lidocaine derivative QX-314, leading to TLR5-dependent blockade of sodium currents predominantly in A-fiber neurons of mouse DRGs. Intraplantar co-application of flagellin and QX-314 (flagellin/QX-314) dose-dependently suppressed mechanical allodynia following chemotherapy, nerve injury, and diabetic neuropathy, but this blockade is abrogated in Tlr5-deficient mice. In vivo electrophysiology demonstrated that flagellin/QX-314 co-application selectively suppressed Aβ-fiber conduction in naive and chemotherapy-treated mice. TLR5-mediated Aβ blockade but not capsaicin-mediated C-fiber blockade also reduced chemotherapy-induced ongoing pain without impairing motor function. Finally, flagellin/QX-314 co-application suppressed sodium currents in large-diameter human DRG neurons. Thus, our findings provide a new tool for targeted silencing of Aβ-fibers and neuropathic pain treatment.