title: 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.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.|Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Zhen-Zhong
authors.initials: ZZ
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.|Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.|Pain Cognitive Function Research Center, Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.|Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Sangsu
authors.initials: S
authors.lastname: Bang
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.|Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Temugin
authors.initials: T
authors.lastname: Berta
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Pain Cognitive Function Research Center, Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, Republic of Korea.|Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seog Bae
authors.initials: SB
authors.lastname: Oh
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.|Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
mesh_terms: D000328:Adult; D000368:Aged; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002211:Capsaicin / Q000494:pharmacology; D003929:Diabetic Neuropathies / Q000150:complications; D005260:Female; D005408:Flagellin / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects; D009437:Neuralgia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017239:Paclitaxel / Q000633:toxicity; D059348:Peripheral Nerve Injuries / Q000150:complications; D018689:Sensory System Agents / Q000494:pharmacology; D051198:Toll-Like Receptor 5 / Q000235:genetics*
chemical_list: D000779:Anesthetics, Local; D000970:Antineoplastic Agents; D016900:Neurofilament Proteins; D018689:Sensory System Agents; D051198:Toll-Like Receptor 5; C051774:neurofilament protein H; D005408:Flagellin; C012647:QX-314; D008012:Lidocaine; D017239:Paclitaxel; D002211:Capsaicin