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

Nat Med. 2015 Nov;21(11):1326-31. doi: 10.1038/nm.3978. Epub 2015 Oct 19.


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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anesthetics, Local / pharmacology*
  • Animals
  • Antineoplastic Agents / toxicity
  • Capsaicin / pharmacology
  • Diabetic Neuropathies / complications
  • Female
  • Flagellin / pharmacology*
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / drug effects*
  • Ganglia, Spinal / metabolism
  • Humans
  • Hyperalgesia / etiology
  • Hyperalgesia / genetics*
  • Hyperalgesia / metabolism
  • Lidocaine / analogs & derivatives*
  • Lidocaine / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Nerve Fibers, Myelinated / drug effects*
  • Nerve Fibers, Myelinated / metabolism
  • Nerve Fibers, Unmyelinated / drug effects
  • Neuralgia / etiology
  • Neuralgia / genetics*
  • Neuralgia / metabolism
  • Neurofilament Proteins / metabolism
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Paclitaxel / toxicity
  • Peripheral Nerve Injuries / complications
  • Sensory System Agents / pharmacology
  • Toll-Like Receptor 5 / genetics*


  • Anesthetics, Local
  • Antineoplastic Agents
  • Neurofilament Proteins
  • Sensory System Agents
  • Toll-Like Receptor 5
  • neurofilament protein H
  • Flagellin
  • QX-314
  • Lidocaine
  • Paclitaxel
  • Capsaicin