Differential modulation of Na v 1.7 and Na v 1.8 peripheral nerve sodium channels by the local anesthetic lidocaine

Voltage‐gated Na + channels are transmembrane proteins that are essential for the propagation of action potentials in excitable cells. Na v 1.7 and Na v 1.8 dorsal root ganglion Na + channels exhibit different kinetics and sensitivities to tetrodotoxin (TTX). We investigated the properties of both channels in the presence of lidocaine, a local anesthetic (LA) and class I anti‐arrhythmic drug. Na v 1.7 and Na v 1.8 Na + channels were coexpressed with the β 1 ‐subunit in Xenopus oocytes. Na + currents were recorded using the two‐microelectrode voltage‐clamp technique. Dose–response curves for both channels had different EC 50 (dose producing 50% maximum current inhibition) (450 μ M for Na v 1.7 and 104 μ M for Na v 1.8). Lidocaine enhanced current decrease in a frequency‐dependent manner. Steady‐state inactivation of both channels was also affected by lidocaine, Na v 1.7 being the most sensitive. Only the steady‐state activation of Na v 1.8 was affected while the entry of both channels into slow inactivation was affected by lidocaine, Na v 1.8 being affected to a larger degree. Although the channels share homology at DIV S6, the LA binding site, they differ in their sensitivity to lidocaine. Recent studies suggest that other residues on DI and DII known to influence lidocaine binding may explain the differences in affinities between Na v 1.7 and Na v 1.8 Na + channels. Understanding the properties of these channels and their pharmacology is of critical importance to developing drugs and finding effective therapies to treat chronic pain.British Journal of Pharmacology (2004) 142 , 576–584. doi: 10.1038/sj.bjp.0705796