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ANESTHETIC PHARMACOLOGY

Lidocaine and Octanol Have Different Modes of Action at Tetrodotoxin-Resistant Na⁺ Channels of Peripheral Nerves

Deniz Poyraz, MD^*, Michael E. Bräu, PD MD, Friederike Wotka, Cand Med^*, Birgit Puhlmann, MD^*, Andreas M. Scholz, PD MD, Prof. Gunter Hempelmann, MD, Prof. Wolfgang J. Kox, MD PhD^*, and Prof. Claudia D. Spies, MD^*

*Department of Anesthesiology and Intensive Care Medicine, University Hospital Charité Campus Mitte, Humboldt University, Berlin, Germany; Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital, Justus-Liebig-University, Giessen, Germany; and Department of Physiology, Justus-Liebig-University, Giessen, Germany

Address correspondence and reprint requests to Claudia D. Spies, MD, Department of Anesthesiology and Intensive Care Medicine, University Hospital Charité Campus Mitte, Humboldt University, Schumannstr. 20/21, 10117 Berlin, Germany. Address e-mail to claudia.spies{at}charite.de

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 µM, 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 µM). 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.

IMPLICATIONS: 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.

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