Selective cold pain inhibition by targeted block of TRPM8-expressing neurons with quaternary lidocaine derivative QX-314

Abstract

Treatment of pain with local anesthetics leads to an unfavorable decrease in general sensory acuity due to their indiscriminate block of both pain sensing (nociceptors) and non-pain sensing nerves. However, the cell impermeant lidocaine derivative QX-314 can be selectively targeted to only nociceptors by permeation through ligand-gated cation channels. Here we show that localized injection of QX-314 with agonists for the menthol receptor TRPM8 specifically blocks cold-evoked behaviors in mice, including cold allodynia and hyperalgesia. Remarkably, cooling stimuli also promotes QX-314-mediated inhibition of cold behaviors, and can be used to block cold allodynia, while retaining relatively normal cold sensation. The effects of both agonist and thermally evoked uptake of QX-314 are TRPM8-dependent, results demonstrating an effective approach to treat localized cold pain without altering general somatosensation.

Dominant Role of the Gut Microbiota in Chemotherapy Induced Neuropathic Pain

“…Control animals received an equivalent volume of the vehicle. To determine the induction of CIPN, we tested these animals sensitivity to thermal (heat and cold) and mechanical stimuli at 3, 10, and 15 days after the initial Paclitaxel injection 26,27 . B6 mice exhibited mechanical allodynia (Fig.…”

“…To measure cold sensitivity of the hind paws, the cold plantar assay was performed as previously described 27,55 . Briefly, mice were allowed to acclimate in Plexiglas chambers for 2 hours prior to cold plantar testing performed at room temperature.…”

“…To test heat sensitivity, the Hargreaves assay was performed 26,27 . Mice were allowed to acclimate in Plexiglas chamber on a glass plate heated to 32 °C for 30 min.…”

Atractylodin Produces Antinociceptive Effect through a Long-Lasting TRPA1 Channel Activation

“…Although the TRPA1 channel is activated by a variety of environmental irritants and is related to chemical-evoked pain, the contribution of the TRPA1 channel for detecting noxious mechanical and noxious cold pain is still controversial [ 35 ]. Previous studies have shown that QX-314 enters the cell through the TRP channels and increases mechanical, heat, and cold pain thresholds by blocking sodium channels in vivo [ 23 , 26 , 36 ]. Kobayashi et al [ 35 ] reported that approximately 66.7% of TRPV1-expressing DRG neurons co-express TRPA1 channels, and 100% of TRPA1-expressing DRG neurons co-express TRPV1 channels.…”

Regulation of the cold-sensing TRPM8 channels by phosphoinositides and Gq-coupled receptors

“…Genetic deletion of TRPM8 in mice revealed that this channel is important for sensing moderately cold temperatures [6][7][8]. Later studies showed that the channel is also involved in pathological cold sensation [9,10].…”