Inhibitory effect of gabapentin on N-methyl-D-aspartate receptors expressed in Xenopus oocytes
Inhibitory effect of gabapentin on N-methyl-D-aspartate receptors expressed in Xenopus oocytes
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DOI：
10.1111/j.1399-6576.2006.01183.x
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发表时间：
2007-01-01
影响因子：
2.1
通讯作者：
Sata, T.
中科院分区：
文献类型：
--
作者：
Hara, K.;Sata, T.
背景：加巴喷丁(GBP)是一种用于治疗神经病理性和术后疼痛的处方药。然而，其发挥镇痛作用的机制尚不清楚。由于鞘内给予GBP在动物实验中已被证明具有抗伤害效应，我们假设脊髓可能是一个合理的作用部位。方法：我们观察了GBP对分布在脊髓中并参与痛觉调制的神经递质门控离子通道和G蛋白偶联内向整流钾通道(GIRK)的影响。重组人NR1/NR2A型N-甲基-d-天冬氨酸(NMDA)、α(1)β(2)γ(2S)γ-氨基丁酸A型(GABA(A))或α(1)甘氨酸受体或GIRK1/GIRK2通道在非洲爪哇卵母细胞中表达，并用双电极电压钳系统观察GBP(0.1-1000mM)对其的影响。反之，GBP以浓度依赖的方式抑制NMDA受体，在10 mM时有明显的抑制作用。在30 mM时，GBP抑制谷氨酸浓度反应曲线，而不改变半数有效浓度或Hill系数，表明非竞争性抑制。结论：GBP对NMDA受体的抑制作用可能在GBP的抗伤害性作用中起重要作用，而GABA(A)、甘氨酸受体或GIRK通道可能不参与GBP的药理作用。
Background: Gabapentin (GBP) is a prescription drug used for the treatment of neuropathic and post-operative pain. However, the mechanism by which it exerts its analgesic action is not well understood. Because intrathecal administration of GBP has been shown to exert antinociceptive effects in animal studies, we hypothesized that the spinal cord may be a plausible action site.Methods: We examined the effects of GBP on neurotransmitter-gated ion channels and G protein-coupled inwardly rectifying potassium (GIRK) channels distributed in the spinal cord and involved in pain modulation. Recombinant human NR1/NR2A N-methyl-d-aspartate (NMDA), alpha(1)beta(2)gamma(2S) gamma-aminobutyric acid type A (GABA(A)) or alpha(1) glycine receptors, or GIRK1/GIRK2 channels were expressed in Xenopus laevis oocytes and the effects of GBP (0.1-1000 mu M) on them were assessed using a two-electrode, voltage-clamp system.Results: GABA(A) and glycine receptors and GIRK channels were not affected by GBP, even at the highest concentrations. Conversely, NMDA receptors were inhibited by GBP in a concentration-dependent manner, with significant inhibition observed at 10 mu M. At 30 mu M, GBP inhibited the glutamate-concentration response curve without changing the half-maximal effective concentration or the Hill coefficient, indicating a non-competitive inhibition. Glycine decreased the inhibitory effect in a concentration-dependent manner.Conclusions: These findings suggest that the inhibitory effect of GBP on NMDA receptors may play an important role in the antinociceptive property of GBP; however, it does not appear that GABA(A) and glycine receptors or GIRK channels contribute to the pharmacological properties of GBP.