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 allodynia1,2,3,4. Although large, myelinated group A fibers, in particular Aβ-fibers, have previously been implicated in mechanical allodynia5,6,7, 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 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.
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This study is supported by US National Institutes of Health (NIH) R01 grants NS67686 (R.-R.J.), NS87988 (R.-R.J.), NS89479 (R.-R.J.), DE17794 (R.-R.J.), and DE22743 (R.-R.J.); NIH R21 grants NS82985 (Z.-Z.X.) and NS91779 (Z.-Z.X.); NIH R01 grant DE19440 (F.W.); a Korea government grant 2012R1A3A2048834 (S.B.O.); and a Korea National Research Foundation grant 2013R1A6A3A04065858 (Y.H.K.).
The authors declare no competing financial interests.
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Xu, ZZ., Kim, Y., Bang, S. et al. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat Med 21, 1326–1331 (2015). https://doi.org/10.1038/nm.3978
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