Department of Anesthesiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
Anesthesiology. 2012 Jan;116(1):147-58. doi: 10.1097/ALN.0b013e31823cf233.
Lidocaine exerts antinociceptive effects when applied systemically. The mechanisms are not fully understood but glycinergic mechanisms might be involved. The synaptic glycine concentration is controlled by glycine transporters. Whereas neurons express two types of glycine transporters, astrocytes specifically express glycine transporter 1 (GlyT1). This study focuses on effects of lidocaine and its major metabolites on GlyT1 function.
The effects of lidocaine and its metabolites monoethylglycinexylidide (MEGX), glycinexylidide, and N-ethylglycine on GlyT1 function were investigated in uptake experiments with [¹⁴C]-labeled glycine in primary rat astrocytes. Furthermore, the effect of lidocaine and its metabolites on glycine-induced currents were investigated in GlyT1-expressing Xenopus laevis oocytes.
Lidocaine reduced glycine uptake only at toxic concentrations. The metabolites MEGX, glycinexylidide, and N-ethylglycine, however, significantly reduced glycine uptake (P < 0.05). Inhibition of glycine uptake by a combination of lidocaine with its metabolites at a clinically relevant concentration was diminished with increasing extracellular glycine concentrations. Detailed analysis revealed that MEGX inhibits GlyT1 function (P < 0.05), whereas N-ethylglycine was identified as an alternative GlyT1 substrate (EC₅₀ = 55 μM).
Although lidocaine does not function directly on GlyT1, its metabolites MEGX and N-ethylglycine [corrected] were shown to inhibit GlyT1-mediated glycine uptake by at least two different mechanisms. Whereas N-ethylglycine [corrected] was demonstrated to be an alternative GlyT1 substrate, MEGX was shown to inhibit GlyT1 activity in both primary astrocytes and in GlyT1-expressing Xenopuslaevis oocytes at clinically relevant concentrations. These findings provide new insights into the possible mechanisms for the antinociceptive effect of systemic lidocaine.
利多卡因全身应用时具有镇痛作用。其机制尚未完全阐明，但可能涉及甘氨酸能机制。突触甘氨酸浓度受甘氨酸转运体控制。神经元表达两种类型的甘氨酸转运体，而星形胶质细胞特异性表达甘氨酸转运体 1（GlyT1）。本研究重点关注利多卡因及其主要代谢物对 GlyT1 功能的影响。
在原代大鼠星形胶质细胞摄取实验中，用[¹⁴C]标记甘氨酸研究利多卡因及其代谢物单乙基甘氨酰二甲苯（MEGX）、甘氨酰二甲苯和 N-乙基甘氨酸对 GlyT1 功能的影响。此外，还研究了利多卡因及其代谢物对 GlyT1 表达的非洲爪蟾卵母细胞中甘氨酸诱导电流的影响。
利多卡因仅在毒性浓度下才会减少甘氨酸摄取。然而，代谢物 MEGX、甘氨酰二甲苯和 N-乙基甘氨酸显著减少甘氨酸摄取（P < 0.05）。在临床相关浓度下，利多卡因与其代谢物联合使用抑制甘氨酸摄取，随着细胞外甘氨酸浓度的增加而减弱。详细分析表明，MEGX 抑制 GlyT1 功能（P < 0.05），而 N-乙基甘氨酸被鉴定为 GlyT1 的替代底物（EC₅₀ = 55 μM）。
尽管利多卡因本身不能直接作用于 GlyT1，但已证明其代谢物 MEGX 和 N-乙基甘氨酸[更正]通过至少两种不同的机制抑制 GlyT1 介导的甘氨酸摄取。虽然 N-乙基甘氨酸[更正]被证明是 GlyT1 的替代底物，但 MEGX 被证明在临床相关浓度下在原代星形胶质细胞和 GlyT1 表达的非洲爪蟾卵母细胞中抑制 GlyT1 活性。这些发现为系统给予利多卡因的镇痛作用的可能机制提供了新的见解。
