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REGIONAL ANESTHESIA AND PAIN MEDICINE

Block of Neuronal Tetrodotoxin-Resistant Na+ Currents by Stereoisomers of Piperidine Local Anesthetics

Michael E. Bräu, PD Dr. med.^*, Pierre Branitzki, Andrea Olschewski, Dr. med.^*, Werner Vogel, Prof. Dr. rer. nat., and Gunter Hempelmann, Prof. Dr. med., Dr. h.c.^*

Departments of *Anesthesiology and Intensive Care Medicine and Physiology, Justus-Liebig-University, Giessen, Germany

Address correspondence and reprint requests to Michael E. Bräu, PD Dr. med, Abteilung Anaesthesiologie und Operative Intensivmedizin Justus-Liebig-Universität, Rudolf-Buchheim-Str. 7, D-35385 Giessen, Germany. Address e-mail to meb{at}anesthesiology.de

Tetrodotoxin (TTX)-sensitive Na⁺ channels in the peripheral nervous system are the major targets for local anesthetics. In the peripheral nociceptive system, a Na⁺ channel subtype resistant to TTX and with distinct electrophysiological properties seems to be of importance for impulse generation and conduction. A current through TTX-resistant Na⁺ channels displays slower activation and inactivation kinetics and has an increased activation threshold compared with TTX-sensitive Na⁺ currents and may have different pharmacological properties. We studied the effects of stereoisomers of piperidine local anesthetics on neuronal TTX-resistant Na⁺ currents recorded with the whole-cell configuration of the patch clamp method in enzymatically dissociated dorsal root ganglion neurons of adult rats. Stereoisomers of mepivacaine, ropivacaine, and bupivacaine reversibly inhibited TTX-resistant Na⁺ currents in a concentration and use-dependent manner. All drugs accelerated time course of inactivation. Half-maximal blocking concentrations were determined from concentration-inhibition relationships. Potencies for tonic and for use-dependent block increased with rising lipid solubilities of the drugs. Stereoselective action was not observed. We conclude that block of TTX-resistant Na⁺ currents may lead to blockade of TTX-resistant action potentials in nociceptive fibers and consequently may be responsible for pain suppression during local anesthesia.

Implications: Tetrodotoxin-resistant Na⁺ channels are important in peripheral nociception. During local anesthesia, these channels are blocked by mepivacaine, ropivacaine, and bupivacaine in a concentration and use-dependent manner, but not stereoselectively.

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