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ANALGESIA

Mexiletine and Lidocaine Suppress the Excitability of Dorsal Horn Neurons

Andrea Olschewski, MD, PhD^*, Rose Schnoebel-Ehehalt, MD^*, Yingji Li, MD, PhD, Bi Tang, MD, Michael E. Bräu, MD, PhD^*, and Matthias Wolff, MD, PhD^*

From the *Departments of Anaesthesiology, Intensive Care Medicine, Pain Therapy, University Clinic Giessen and Marburg GmbH, Giessen, Germany; Experimental Anaesthesiology, University Clinic of Anaesthesia and Intensive Care Medicine, Medical University of Graz, Austria; Department of Pulmonology, University Clinic of Internal Medicine, Medical University of Graz, Austria; and Department of Physiology, Justus-Liebig-University, Giessen, Germany.

Address correspondence and reprint requests to Andrea Olschewski, MD, PhD, Department of Anesthesiology, University Clinic of Anaesthesiology and Intensive Care Medicine, Medical University Graz, Auenbruggerplatz 29, A-8036 Graz, Austria. Address e-mail to andrea.olschewski{at}medunigraz.at.

Abstract

BACKGROUND: Spinal sensitization and facilitatory processes in dorsal horn neurons after nerve injury alter spinal outflow leading to enhanced pain perception and chronic pain syndromes. Clinically used Na⁺ channel blockers at doses which do not block conduction can relieve such chronic pain. Although much attention has been paid to their effect upon afferents, less work has been done with their effect on the excitability of central sensory neurons. Thus, we investigated the effects of the Na⁺ channel blockers mexiletine and lidocaine on sensory spinal dorsal horn neurons.

METHODS: Patch-clamp recordings were directly performed in visualized neurons of the substantia gelatinosa in the spinal cord of young rats to investigate the effect of mexiletine and lidocaine in different types of dorsal horn neurons (tonically firing, adapting-firing, and single spike neurons).

RESULTS: All three different types of neurons responded dose-dependently to mexiletine and lidocaine. Both local anesthetics reversibly inhibited Na⁺ and K⁺ currents. The half-maximal inhibitory concentration for Na⁺ conductance block was 89 ± 2 or 54 ± 6 µM and for delayed-rectifier K⁺ conductance block was 582 ± 36 or 398 ± 14 µM for lidocaine and mexiletine, respectively. The inhibition of Na⁺ and K⁺ currents consecutively altered the properties of single action potentials and reduced the firing rate of tonically firing and adapting-firing neurons.

CONCLUSIONS: In clinically relevant concentrations, lidocaine and mexiletine reduced the excitability of sensory dorsal horn neurons via a blockade of Na⁺ and K⁺ channels. Our work confirms that, in addition to the peripheral effects of lidocaine and mexiletine, modulation of voltage-gated ion channels in the central nervous system contributes to the antinociceptive effects of these drugs used in pain therapy.