Molecular and systemic mechanisms of general anaesthesia: the 'multi-site and multiple mechanisms' concept a
Molecular and systemic mechanisms of general anaesthesia: the 'multi-site and multiple mechanisms' concept a
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DOI：
10.1097/01.aco.0000174961.90135.dc
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发表时间：
2005-08-01
影响因子：
2.5
通讯作者：
Antkowiak, Bernd
中科院分区：
文献类型：
--
作者：
Grasshoff, Christian;Rudolph, Uwe;Antkowiak, Bernd
综述目的健忘、催眠和静止是全身麻醉的重要组成部分。这篇综述重点介绍了我们在分子水平上了解这些成分的最新进展。最近的发现最近使用的挥发性麻醉剂，如异氟醚或七氟烷，通过调节主要位于脊髓的多个分子靶点而导致不动，包括伽马氨基丁酸(A)受体、甘氨酸受体、谷氨酸受体和Trek-1钾通道。相比之下，静脉注射异丙酚或依托咪酯等药物几乎完全通过增强γ-氨基丁酸(A)受体功能来抑制脊髓运动反射。对敲打动物的研究表明，依托咪酯和异丙酚通过含有β(3)亚基的伽马氨基丁酸(A)受体起作用，而包括α(2)和伽马亚基的伽马氨基丁酸(A)受体介导地西潘的肌松特性。这些发现表明，脊髓中很大一部分γ-氨基丁酸(A)受体由α(2)、β(3)和最有可能的伽马(2)亚单位组成。依托咪酯的催眠作用是由大脑中表达的含有β(3)的伽马氨基丁酸(A)受体介导的。相反，含有β(2)亚基的γ-氨基丁酸(A)受体能产生镇静，但不能催眠。此外，越来越多的证据表明，海马体中含有α(5)亚单位的突触外g-氨基丁酸(A)受体与遗忘有关。失忆、催眠和静止涉及不同的分子靶点，这一发现为开发改进的麻醉治疗策略开辟了新的途径。
Purpose of reviewAmnesia, hypnosis and immobility are essential components of general anaesthesia. This review highlights recent advances in our understanding of how these components are achieved at a molecular level.Recent findingsCommonly used volatile anaesthetic agents such as isoflurane or sevoflurane cause immobility by modulating multiple molecular targets predominantly in the spinal cord, including gamma-aminobutyric acid(A) receptors, glycine receptors, glutamate receptors and TREK-1 potassium channels. In contrast, intravenously applied drugs such as propofol or etomidate depress spinal motor reflexes almost exclusively via enhancing gamma-aminobutyric acid(A) receptor function. Studies on knock-in animals showed that etomidate and propofol act via gamma-aminobutyric acid(A) receptors containing beta(3) subunits, whereas gamma-aminobutyric acid(A) receptors including alpha(2) and gamma subunits mediate the myorelaxant properties of diazepam. These findings suggest that a large fraction of gamma-aminobutyric acid(A) receptors in the spinal cord assemble from alpha(2), beta(3) and most probably gamma(2) subunits. The hypnotic actions of etomidate are mediated by beta(3)-containing gamma-aminobutyric acid(A) receptors expressed in the brain. In contrast, gamma-aminobutyric acid(A) receptors harbouring beta(2) subunits produce sedation, but not hypnosis. Furthermore, there is growing evidence that extrasynaptic g-aminobutyric acid(A) receptors in the hippocampus containing alpha(5) subunits contribute to amnesia.SummaryClinical anaesthesia is based on drug actions at multiple anatomical sites in the brain. The finding that amnesia, hypnosis and immobility involve distinct molecular targets opens new avenues for developing improved therapeutic strategies in anaesthesia.