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

Publication ,  Journal Article
Xu, Z-Z; Kim, YH; Bang, S; Zhang, Y; Berta, T; Wang, F; Oh, SB; Ji, R-R
Published in: Nat Med
November 2015

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.

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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

November 2015

Volume

21

Issue

11

Start / End Page

1326 / 1331

Location

United States

Related Subject Headings

  • Toll-Like Receptor 5
  • Sensory System Agents
  • Peripheral Nerve Injuries
  • Paclitaxel
  • Neurons
  • Neurofilament Proteins
  • Neuralgia
  • Nerve Fibers, Unmyelinated
  • Nerve Fibers, Myelinated
  • Middle Aged
 

Citation

APA
Chicago
ICMJE
MLA
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Xu, Z.-Z., Kim, Y. H., Bang, S., Zhang, Y., Berta, T., Wang, F., … Ji, R.-R. (2015). Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat Med, 21(11), 1326–1331. https://doi.org/10.1038/nm.3978
Xu, Zhen-Zhong, Yong Ho Kim, Sangsu Bang, Yi Zhang, Temugin Berta, Fan Wang, Seog Bae Oh, and Ru-Rong Ji. “Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade.Nat Med 21, no. 11 (November 2015): 1326–31. https://doi.org/10.1038/nm.3978.
Xu Z-Z, Kim YH, Bang S, Zhang Y, Berta T, Wang F, et al. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat Med. 2015 Nov;21(11):1326–31.
Xu, Zhen-Zhong, et al. “Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade.Nat Med, vol. 21, no. 11, Nov. 2015, pp. 1326–31. Pubmed, doi:10.1038/nm.3978.
Xu Z-Z, Kim YH, Bang S, Zhang Y, Berta T, Wang F, Oh SB, Ji R-R. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat Med. 2015 Nov;21(11):1326–1331.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

November 2015

Volume

21

Issue

11

Start / End Page

1326 / 1331

Location

United States

Related Subject Headings

  • Toll-Like Receptor 5
  • Sensory System Agents
  • Peripheral Nerve Injuries
  • Paclitaxel
  • Neurons
  • Neurofilament Proteins
  • Neuralgia
  • Nerve Fibers, Unmyelinated
  • Nerve Fibers, Myelinated
  • Middle Aged