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

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

Xu ZZ1,2, Kim YH1,2,3, Bang S1,2, Zhang Y2, Berta T1,2, Wang F2, Oh SB3,4, Ji RR1,2.

Author information

1
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.
2
Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.
3
Pain Cognitive Function Research Center, Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
4
Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.

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 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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PMID:
26479925
PMCID:
PMC4752254
DOI:
10.1038/nm.3978
[Indexed for MEDLINE]
Free PMC Article

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