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

Abstract

SUMMARY 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 C-fibers has limited effects on mechanical allodynia1–4. While large myelinated A-fibers, in particular Aβ-fibers, have previously been implicated in mechanical allodynia5–7, 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 suppressed mechanical allodynia following chemotherapy, nerve injury, and diabetic neuropathy, but this blockade is abrogated in Tlr5-deficient mice. In vivo electrophysiology demonstrated that flagellin/QX-314 co-application selectively suppressed Aβ-fiber conduction in naive and chemotherapy-treated mice. TLR5-mediated Aβ 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.

Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

“…To produce chemotherapy-associated neuropathic pain, paclitaxel (2 mg/kg, i.p.) was injected at day 0, 2, 4, and 6 (Xu et al, 2015). …”

Etiology and Pharmacology of Neuropathic Pain

“…This may be achieved by direct activation of TRPV1 by capsaicin or indirect activation of other drug-permeable channels via Toll-like receptor 5 (TLR5) (Peirs and Seal, 2015;Xu et al, 2015). The TRPV1 channel pore is large enough to permit permeation of a quaternary derivative of lidocaine known as QX-314.…”

“…It is effective when introduced into the cytoplasm via the TRPV1 channel, and this allows selective targeting of classic C fiber nociceptors in nociceptive pain. Because TLR5 is expressed on medium to large A fibers, including Ab mechanoreceptors in both mice and humans (Xu et al, 2015), this may allow selective pharmacological blockade of transmission in fiber types that mediate allodynia. We recently noted that GBP is able to permeate TRPV1 channels activated by capsaicin, and this led to increased effectiveness (Biggs et al, 2015).…”

“…We recently noted that GBP is able to permeate TRPV1 channels activated by capsaicin, and this led to increased effectiveness (Biggs et al, 2015). Perhaps topical application of GBP (Shahid et al, 2017) combined with a TLR5 agonist such as flagellin (Xu et al, 2015) may facilitate its access to a2d-1 and thereby increase its effectiveness in the clinic.…”

Autoantibodies and pain

“…Because of the process of central sensitisation, large A b fibres are able to engage the nociceptive system, and ectopic activity in sensory neurons, more so in myelinated than unmyelinated fibres, is a hallmark of neuropathic pain caused by peripheral nerve injury [17]. Accordingly, blockade of these large fibres can completely attenuate the allodynia and spontaneous pain in neuropathic pain models [18]. LGI1 antibodies were also reported in some patients with pain [3] but their significance is less easy to assess as LGI1 is not typically expressed at nodes of Ranvier or known to play a role in peripheral nerve, dorsal roots or spinal cord.…”