MK-801 enhances gabaculine-induced loss of the righting reflex in mice, but not immobility
MK-801 enhances gabaculine-induced loss of the righting reflex in mice, but not immobility
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DOI：
10.1007/bf03016634
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发表时间：
2007-12-01
期刊：
影响因子：
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通讯作者：
Kawahara, Michio
中科院分区：
文献类型：
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作者：
Irifune, Masahiro;Katayama, Sohtaro;Kawahara, Michio
目的：γ -氨基丁酸（GABA）和n -甲基- d -天冬氨酸（NMDA）受体是体外细胞水平麻醉作用的重要靶点。Gabaculine是一种GABA转氨酶抑制剂，可增加大脑内源性GABA，并增强GABA活性。我们最近的研究表明，无意识与GABA活性的增强有关，这是由于gabaculine的作用，但不动与此无关。MK-801是一种选择性NMDA通道阻滞剂。在这项研究中，我们从行为上检查了加巴库林与MK-801联合使用是否能产生这些全麻状态的成分。我们进一步比较了MK-801与另一种NMDA通道阻滞剂氯胺酮的效果。方法：所有药物均予成年雄性小鼠腹腔注射。为了评估全麻成分，使用了两个终点。一种是失去翻正反射（LORR，作为无意识的衡量标准），另一种是对尾钳刺激的反应失去运动能力（作为不动的衡量标准）。结果：大剂量MK-801单独（10-50 mg.kg(-1)）既不会引起LORR，也不会引起对有害刺激的不活动。然而，即使是小剂量（0.2 mg.kg(-1)）也显著增强了gabaculine诱导的LORR (P < 0.05)，尽管gabaculine与MK-801 （0.2-10 mg.kg(-1)）联合使用不会产生不动。然而，加巴库林加亚麻醉剂量氯胺酮（30 mg.kg(-1)）作用于NMDA、阿片和尼古丁乙酰胆碱受体以及神经元Na+通道，抑制了疼痛反应，但没有达到完全的效果。氯胺酮单独剂量依赖产生LORR和不动。结论：这些研究结果表明，gabaculine诱导的LORR可通过阻断NMDA受体来调节，但不动性不是通过GABA或NMDA受体介导的。
Purpose: gamma-Aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors are important targets for anesthetic action at the in vitro cellular level. Gabaculine is a GABA-transaminase inhibitor that increases endogenous GABA in the brain, and enhances GABA activity. We have recently shown that unconsciousness is associated with the enhanced GABA activity due to gabaculine, but that immobility is not. MK-801 is a selective NMDA channel blocker. In this study, we examined behaviourally whether gabaculine in combination with MK-801 could produce these components of the general anesthetic state. We further compared the effect of MK-801 with ketamine, another NMDA channel blocker.Methods: All drugs were administered intraperitoneally to adult male ddY mice. To assess the general anesthetic components, two endpoints were used. One was loss of the righting reflex (LORR; as a measure of unconsciousness) and the other was loss of movement in response to tail-clamp stimulation (as a measure of immobility).Results: Large doses of MK-801 alone (10-50 mg.kg(-1)) induced neither LORR nor immobility in response to noxious stimulation. However, even a small dose (0.2 mg.kg(-1)) significantly enhanced gabaculine-induced LORR (P < 0.05), although gabaculine in combination with MK-801 (0.2-10 mg.kg(-1)) produced no immobility. However, gabaculine plus a subanesthetic dose of ketamine (30 mg.kg(-1)), which acts on NMDA, opioid and nicotinic acetylcholine receptors and neuronal Na+ channels, suppressed the pain response, but did not achieve a full effect. Ketamine alone dose-dependently produced both LORR and immobility.Conclusion: These findings suggest that gabaculine-induced LORR is modulated by blocking NMDA receptors, but that immobility is not mediated through GABA or NMDA receptors.