Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurones
Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurones
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DOI：
10.1038/sj.bjp.0704439
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发表时间：
2002-01-01
影响因子：
7.3
通讯作者：
Scott, RH
中科院分区：
文献类型：
--
作者：
Sutton, KG;Martin, DJ;Scott, RH
1本研究检查了加巴喷丁的作用（加巴喷丁，1-（氨甲基）环己烷乙酸（Neurontin（R））对培养的大鼠背根神经节（DRG）神经元中记录的电压门控钙（Ca 2+）通道内流的影响。2使用基于Fura-2的荧光Ca 2+成像和全细胞膜片钳技术监测电压门控Ca 2+内流。瞬态显示加巴喷丁抑制KCl（30 mm）诱发的电压依赖性Ca 2+内流。在加巴喷丁（25 μ M）存在下，50%最大响应的持续时间（W50）和总Ca 2+内流均显著减少了25 -30%。4加巴喷丁以剂量依赖性方式有效抑制峰值全细胞Ca 2+通道电流（I-Ba），估计IC 50值为167 μ m。在最大浓度为25 μ M时，阻断是不完全和饱和的。5在中性氨基酸L-异亮氨酸（25 μ M）存在时，抑制作用显著降低，但不受GABA（B）拮抗剂萨氯芬（200 μ M）的影响，表明对Ca 2+通道的α（2）δ亚基有直接作用。6加巴喷丁抑制作用是电压依赖性的，在电流电压特性中产生类似于7 mV的超极化偏移，并减少在相对去极化电位下激活的全细胞电流的非失活成分。7特异性Ca 2+通道拮抗剂的使用揭示了加巴喷丁敏感电流的混合药理学8本研究首次证明加巴喷丁直接介导DRG神经元电压门控性Ca 2+内流的抑制，为加巴喷丁有效介导脊髓抗伤害性感受提供了潜在手段。
1 This study examined the action of gabapentin (gabapentin,1-(aminomethyl) cyclohexane acetic acid (Neurontin(R))) on voltage-gated calcium (Ca2+) channel influx recorded in cultured rat dorsal root ganglion (DRG) neurones.2 Voltage-gated Ca2+ influx was monitored using both fura-2 based fluorescence Ca2+ imaging and the whole-cell patch clamp technique.3 Imaging of intracellular Ca2+ transients revealed that gabapentin inhibited KCl (30 mm)-evoked voltage-dependent Ca2+ influx. Both the duration for 50% of the maximum response (W50) and total Ca2+ influx were significantly reduced by similar to25-30% in the presence of gabapentin (25 muM).4 Gabapentin potently inhibited the peak whole-cell Ca2+ channel current (I-Ba) in a dose-dependent manner with an estimated IC50 value of 167 rim. Block was incomplete and saturated at a maximal concentration of 25 muM.5 Inhibition was significantly decreased in the presence of the neutral amino acid L-isoleucine (25 muM) but unaffected by application of the GABA(B) antagonist, saclofen (200 muM), suggesting a direct action on the alpha(2)delta subunit of the Ca2+ channel.6 Gabapentin inhibition was voltage-dependent, producing an similar to 7 mV hyperpolarizing shift in current voltage properties and reducing a non-inactivating component of whole-cell current activated at relatively depolarized potentials.7 The use of specific Ca2+ channel antagonists revealed a mixed pharmacology of the gabapentin-sensitive current (N-, L- and P/Q-type), which is dominated by N-type current.8 The present study is the first to demonstrate that gabapentin directly mediates inhibition of voltage-gated Ca2+ influx in DRG neurones, providing a potential means for gabapentin to effectively mediate spinal anti-nociception.