每周论文更新----23 Sep 2016

zhouxuelong0258

每周论文更新----23 Sep 2016
周伯通博士

本周给大家推荐一篇极其经典的疼痛相关的文章，相信很多人都读过，或者说没读过应该不是做疼痛基础研究的。它就是07年由哈佛大学神经生物研究所Bruce Bean教授发表在Nature杂志上题为"Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers"的文章。文章极其有创意，以至于当年被Nature杂志评为年度文章。无独有偶，15年Duke大学纪如荣教授实验室依此文章为模板发表了一篇Nature Medicine杂志的文章。07年的文章大意如下：临床上所用的镇痛药物最为有效的是阿片类药物以及局麻药。阿片药物副反应很多，很多做基础研究的都在开发新的药物靶点来替代阿片药物，但是进展很缓慢。近30年，只有加巴喷丁和普瑞巴林效果还不错，其他开发的镇痛药物作用都很不理想；局麻药镇痛效果也很好，但是有一个缺点，就是阻断痛觉的同时也把运动觉给阻断了，所以往往硬膜外或者腰麻过后病人的肢体制动。如果有一种方法可以让局麻药只阻断痛觉而不阻断运动觉，这该有多好啊！文章作者于是发现了一种利多卡因的衍生物QX-314。大家都知道利多卡因能够与神经元的钠离子通道结合抑制其活性，这种抑制作用只需要利多卡因在细胞外结合钠离子通道就能实现，因此利多卡因抑制钠通道是一种非特异的方式，不管什么神经元都能抑制。但是，QX-314如果要发挥钠通道阻断作用必须进入到细胞内，结合细胞内的钠通道。因此，如果能让QX-314选择性的只进入痛觉神经元，而不进入运动神经元，就可能实现局麻药QX-314只镇痛而不阻滞运动的作用了。大家都知道TRPV1离子通道参与疼痛或者就是疼痛通道，表达TRPV1的神经元很大程度上代表疼痛神经元，运动神经元上基本没有TRPV1表达。因此，如果用一定剂量的TRPV1激动剂打开该通道，让QX-314选择性的进入到疼痛神经元里面阻断钠离子通道，这样就能够实现特性性的阻断痛觉，而不阻断运动觉了。于是，作者根据以上假设开展了相应的实验研究，并最终取得了预想中的结果。15年纪如荣实验室的文章则换了个思路，用激动剂选择性的打开了特异性表达在Aβ神经元上的TLR5，通过TLR5让QX-314进入到神经元内，最终实现了选择性的阻断神经病理性疼痛中机械痛觉异常的效果。

哈佛大学神经生物研究所Bruce Bean教授文章

Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers.

通过TRPV1介导的非通透性钠离子通道阻断剂的进入实现伤害性感受器的选择性抑制

Binshtok AM, Bean BP, Woolf CJ.

Nature. 2007 Oct 4

PMID: 17914397

Abstract

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. 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.

                               
登录/注册后可看大图

全文链接：http://www.nature.com/nature/jou ... ll/nature06191.html

杜克大学麻醉学系纪如荣教授文章

Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade.

通过TLR5介导的A纤维阻断实现选择性的抑制神经病理性疼痛机械痛觉异常

Xu ZZ, Kim YH, Bang S, Zhang Y, Berta T, Wang F, Oh SB, Ji RR.

Nat Med. 2015 Nov;21

PMID: 26479925

Abstract

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 group C nerve fibers (C-fibers) has limited effects on mechanical allodynia. Although large, myelinated group 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 blockadeof sodium currents, predominantly in A-fiber neurons of mouse DRGs. Intraplantar co-application of flagellin and QX-314 (flagellin/QX-314) dose-dependently suppresses mechanical allodynia after chemotherapy, nerve injury, and diabetic neuropathy, but this blockade is abrogated in Tlr5-deficient mice. In vivo electrophysiology demonstrated that co-application of flagellin/QX-314 selectively suppressed Aβ-fiber conduction in naive and chemotherapy-treated mice. TLR5-mediated Aβ-fiber 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.

                               
登录/注册后可看大图

全文链接：http://www.nature.com/nm/journal/v21/n11/full/nm.3978.html

Tips：Bruce Bean教授来自哈佛大学神经生物研究所。而现在在杜克大学供职的纪如荣教授也曾经在哈佛大学神经生物研究所下面待过一段时间，当时其隶属于Clifford Woolf组。所以他们曾经也算是同事。Bruce Bean教授全美唯一的两个专职疼痛研究的科学院院士之一，另一位则是非常有名的UCSF的David Julius教授。

这里是服务疼痛基础研究科研人员的微信号“疼痛研究论坛”。我们：

• 关注疼痛基础研究进展
• 推荐高水平前沿研究
• 为疼痛基础研究人员提供交流平台
  
  

欢迎长按二维码关注。

登录/注册后可看大图

麻醉杨洋洋

很好有启发～