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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.

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