Maneuf Yannick P, Hughes John, McKnight Alexander T
Pfizer Global Research & Development, Cambridge Laboratories, Cambridge University Forvie Site, Robinson Way, Cambridge CB2 2QB, UK.
Pain. 2001 Aug;93(2):191-196. doi: 10.1016/S0304-3959(01)00316-5.
The effect of gabapentin on the release of the spinal sensory neurotransmitter glutamate has been investigated in an in vitro model using a perfused thin slice preparation from the rat brainstem containing the spinal trigeminal caudal subnucleus (Sp5C) and pre-incubated with [(3)H]glutamate. Addition of excess K(+) to the perfusing solution increased the content of tritium in the perfusate. The prior addition of substance P increased this index of glutamate release in a concentration-dependent manner, with the mean maximum of around 50% increase obtained at 1-3 microM. The action of substance P to increase the evoked release of glutamate was blocked by the antagonist CP-99994, suggesting a specific involvement of the NK(1) receptor in mediating the facilitatory effect. On its own, gabapentin at up to 100 microM did not modify the baseline level of K(+)-evoked release of glutamate; however, gabapentin caused a concentration-dependent decrease of the facilitatory effect of substance P (EC(50)=6.49 microM). The R-(-)- and S-(+)-isomers of 3-isobutylgaba were then tested against the increase in K(+)-evoked release of glutamate by substance P. S-(+)-3-isobutylgaba (pregabalin) at 30 microM acted like gabapentin to reduce the substance P-mediated increase of release almost to the baseline level of K(+)-evoked release, while in contrast the R-(-)-isomer at this concentration produced no reduction, and rather a trend towards a further enhancement of the potentiating effect of substance P. In conclusion, we have found and characterized an effect of gabapentin that is of possible mechanistic relevance to the anti-hyperalgesic/allodynic actions of this compound.
已在体外模型中研究了加巴喷丁对脊髓感觉神经递质谷氨酸释放的影响，该模型使用了来自大鼠脑干的灌注薄片制剂，其中包含脊髓三叉神经尾侧亚核（Sp5C），并预先用[³H]谷氨酸进行孵育。向灌注溶液中添加过量的钾会增加灌注液中的氚含量。预先添加P物质会以浓度依赖的方式增加谷氨酸释放指标，在1 - 3微摩尔时平均最大增加约50%。P物质增加谷氨酸诱发释放的作用被拮抗剂CP - 99994阻断，表明NK(1)受体在介导促进作用中具有特定作用。单独使用时，高达100微摩尔的加巴喷丁不会改变钾诱发的谷氨酸释放的基线水平；然而，加巴喷丁会导致P物质促进作用的浓度依赖性降低（半数有效浓度（EC₅₀）= 6.49微摩尔）。然后测试了3 - 异丁基氨基丁酸的R - (-) - 和S - (+) - 异构体对P物质引起的钾诱发的谷氨酸释放增加的影响。30微摩尔的S - (+) - 3 - 异丁基氨基丁酸（普瑞巴林）的作用与加巴喷丁相似，可将P物质介导的释放增加几乎降低到钾诱发释放的基线水平，而相比之下，该浓度的R - (-) - 异构体没有降低作用，反而有进一步增强P物质增强作用的趋势。总之，我们发现并表征了加巴喷丁的一种作用，其可能与该化合物的抗痛觉过敏/异常性疼痛作用具有机制相关性。
