Anesthetic agent-specific effects on synaptic inhibition.
Anesthetic agent-specific effects on synaptic inhibition.
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DOI：
10.1213/ane.0000000000000321
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发表时间：
2014-09
影响因子：
5.7
通讯作者：
MacIver MB
中科院分区：
文献类型：
--
作者：
MacIver MB
麻醉剂增强中枢神经系统中γ-氨基丁酸（GABA）介导的抑制作用。不同的药物已被证明作用于紧张性与突触GABA受体的程度不同，但它仍然是未知的，是否不同形式的突触抑制也有差异。考虑到这一点，我们测试了不同类型的GABA介导的突触表现出不同的麻醉敏感性的假设。本研究比较了异氟烷、氟烷、戊巴比妥、硫喷妥钠和丙泊酚对成对脉冲GABAA受体介导的突触抑制的影响。还研究了对谷氨酸介导的促进作用的影响。在大鼠海马脑片中测量突触反应。顺向成对脉冲刺激用于评估麻醉对谷氨酸介导的兴奋性输入或GABA介导的抑制性输入到CA 1神经元的影响。逆向刺激用于评估麻醉对CA 1背景兴奋性的影响。在群体峰电位抑制的等效浓度下研究药物，以比较它们对突触抑制的相对影响程度。不同程度的麻醉效果对兴奋性谷氨酸突触的成对脉冲易化是明显的，阻断GABA抑制揭示了戊巴比妥以前看不见的突触前作用。虽然所有五种麻醉剂抑制突触诱发兴奋的CA 1神经元，参与增强GABA介导的抑制剂之间有很大差异。异丙酚、硫喷妥钠和戊巴比妥可增强单脉冲抑制作用，氟烷和异氟烷仅能轻微增强。相反，异氟烷和硫喷妥钠强烈增强配对脉冲抑制，但丙泊酚、戊巴比妥和氟烷的效果较差。这些观察结果支持了这样的观点，即不同的GABA突触使用具有不同亚基组成的受体，并且麻醉剂对这些受体表现出不同程度的选择性。本研究中在谷氨酸和GABA突触处观察到的不同麻醉剂敏感性有助于解释不同类别麻醉剂产生的独特行为/临床特征，并表明新药开发有选择性靶点。
Anesthetics enhance gamma-aminobutyric acid (GABA)-mediated inhibition in the central nervous system. Different agents have been shown to act on tonic versus synaptic GABA receptors to different degrees, but it remains unknown whether different forms of synaptic inhibition are also differentially engaged. With this in mind, we tested the hypothesis that different types of GABA-mediated synapses exhibit different anesthetic sensitivities. The present study compared effects produced by isoflurane, halothane, pentobarbital, thiopental and propofol on paired pulse GABAA receptor-mediated synaptic inhibition. Effects on glutamate-mediated facilitation were also studied. Synaptic responses were measured in rat hippocampal brain slices. Orthodromic paired pulse stimulation was used to assess anesthetic effects on either glutamate-mediated excitatory inputs or GABA-mediated inhibitory inputs to CA1 neurons. Antidromic stimulation was used to assess anesthetic effects on CA1 background excitability. Agents were studied at equi-effective concentrations for population spike depression to compare their relative degree of effect on synaptic inhibition. Differing degrees of anesthetic effect on paired pulse facilitation at excitatory glutamate synapses were evident, and blocking GABA inhibition revealed a previously unseen presynaptic action for pentobarbital. Although all five anesthetics depressed synaptically evoked excitation of CA1 neurons, the involvement of enhanced GABA-mediated inhibition differed considerably among agents. Single pulse inhibition was enhanced by propofol, thiopental and pentobarbital, but only marginally by halothane and isoflurane. In contrast, isoflurane enhanced paired pulse inhibition strongly, as did thiopental, but propofol, pentobarbital and halothane were less effective. These observations support the idea that different GABA synapses use receptors with differing subunit compositions, and that anesthetics exhibit differing degrees of selectivity for these receptors. The differing anesthetic sensitivities seen in the present study, at glutamate and GABA synapses, help explain the unique behavioral/clinical profiles produced by different classes of anesthetics, and indicate that there are selective targets for new agent development.