QX-314 is a membrane-impermeant lidocaine derivative that selectively blocks sodium channels on nociceptive neurons when delivered intracellularly via the TRPV1 channel, but is reportedly ineffective with extracellular application. When supplied in combination with 1 μM capsaicin , a TRPV1 receptor agonist, 5 mM QX-314 blocks 98% of sodium current in voltage-clamped nociceptive DRG neurons. QX-314 elicits a long-lasting decrease in the response to painful mechanical and thermal stimuli without imparting the motor deficits (e.g., numbness, paralysis) associated with many conventional local anesthetics. At concentrations ranging from 10-70 mM, peripheral application of QX-314 dose-dependently produces robust local anesthesia with slow onset in the guinea pig intradermal wheal assay, the mouse tail-flick test, and the mouse sciatic nerve blockade model. However, injection of 0.5-30 mM QX-314 in the lumbar intrathecal space produces neurotoxicity and death in mice.
