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

In Brief 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 α1 glycine, α1β2γ2S γ-aminobutyric acid type A (GABAA), and ρ1 GABAC 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, α1(S267C) and α1(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 GABAA receptor currents, whereas neither lidocaine nor procaine affected GABAC receptor function. CONCLUSIONS: Lidocaine and procaine enhanced glycine receptor function at low concentrations and inhibited the functions of glycine and GABAA 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. IMPLICATIONS: Lidocaine and procaine enhanced glycine receptor function at low concentrations and inhibited glycine and γ-aminobutyric acid type A receptors functions at high concentrations. The mechanism of the local anesthetic (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.