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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Xu, Z-Z; Kim, YH; Bang, S; Zhang, Y; Berta, T; Wang, F; Oh, SB; Ji, R-R

Published Date

  • November 2015

Published In

Volume / Issue

  • 21 / 11

Start / End Page

  • 1326 - 1331

PubMed ID

  • 26479925

Pubmed Central ID

  • 26479925

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

Digital Object Identifier (DOI)

  • 10.1038/nm.3978

Language

  • eng

Conference Location

  • United States