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ANESTHETIC PHARMACOLOGY

The Effects of the Local Anesthetics Lidocaine and Procaine on Glycine and -Aminobutyric Acid Receptors Expressed in Xenopus Oocytes

From the Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.

Address correspondence and reprint requests to Koji Hara, MD, PhD, Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu 807-8555, Japan. Address e-mail to kojihara{at}med.uoeh-u.ac.jp.

BACKGROUND: The voltage-dependent sodium channel is the primary site of action for local anesthetics (LAs). Although systemically administered low-dose LAs have been shown to exert antihyperalgesic effects, the molecular targets responsible for these effects are not fully known and their functional effects on inhibitory neurotransmitter receptors associated with antinociception have not been sufficiently studied.

METHODS: We examined the effects of lidocaine and procaine (0.1 µM to 3 or 10 mM) on recombinant human ₁ glycine, ₁β_22S -aminobutyric acid type A (GABA_A), and ₁ GABA_C receptors expressed in Xenopus laevis oocytes, using a two-electrode voltage-clamp system. We also evaluated the effects of LAs on two mutant glycine receptors, ₁(S267C) and ₁(S267Q), in an effort to clarify the interaction between LAs and glycine receptors.

RESULTS: Low concentrations of both lidocaine and procaine enhanced glycine receptor function, whereas high concentrations of lidocaine and procaine inhibited glycine receptor function. Lidocaine (10 µM) produced a significant leftward shift in the glycine concentration-response curve, indicating an increase in the apparent affinity for glycine. This enhancement was not altered in the mutant receptors. Both lidocaine and procaine at high concentrations inhibited GABA_A receptor currents, whereas neither lidocaine nor procaine affected GABA_C receptor function.

CONCLUSIONS: Lidocaine and procaine enhanced glycine receptor function at low concentrations and inhibited the functions of glycine and GABA_A receptors at high concentrations. The mechanism of the LA-induced enhancement of glycine receptor function probably differs from that of general anesthetics. These findings may explain the pharmacological effects of LAs, such as antinociception and convulsion.