Lidocaine and octanol have different modes of action at tetrodotoxin-resistant Na(+) channels of peripheral nerves.

Abstract

Local anesthetics and alcohols block impulse conduction in peripheral nerves by inhibiting Na(+) currents. In small peripheral nerve fibers, tetrodotoxin-resistant (TTX-r) Na(+) channels play an important role in impulse generation. We investigated the effects of lidocaine and the alcohol octanol on TTX-r Na(+) channels. Currents were recorded with the whole-cell patch-clamp method from enzymatically isolated rat dorsal root ganglion cells (data evaluation: nonlinear least-squares fitting). Lidocaine and octanol blocked the TTX-r Na(+) current in a reversible and concentration-dependent manner (50% inhibitory concentration values: 177 +/- 25 and 455 +/- 25 microM, respectively). Lidocaine additionally produced a strong use-dependent block. Both drugs showed a strong dynamic block (i.e., block developed during the time course of current activation and inactivation). Double-pulse protocols showed a slow dissociation of lidocaine from the channel during repolarization (time constant: 1763 +/- 63 ms; 300 microM). The dissociation of octanol was too quick to be distinguished from normal current repriming kinetics of 2.2 ms. Lidocaine and octanol acted noncompetitively in the Na(+) channel. Lidocaine and octanol have different blocking properties on the TTX-r Na(+) current and bind to different channel sites. Lidocaine and octanol have different inhibitory effects on the function of tetrodotoxin-resistant Na(+) channels in rat dorsal root ganglion cells, as well as noncompetitive modes of action, as investigated by the whole-cell patch-clamp method, and therefore are likely to have different binding sites on the channel.