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

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.

• Authors: Zhen-Zhong Xu, Yong Ho Kim, Sangsu Bang, Yi Zhang, Temugin Berta, Fan Wang, Seog Bae Oh, Ru-Rong Ji
• Journal: Nature medicine (Nat Med) Vol. 21 Issue 11 Pg. 1326-31 (Nov 2015) ISSN: 1546-170X [Electronic] United States
• PMID: 26479925 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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