MacIver M Bruce
From the Department of Anesthesia, Stanford School of Medicine, Palo Alto, California.
Anesth Analg. 2014 Sep;119(3):558-569. doi: 10.1213/ANE.0000000000000321.
Anesthetics enhance γ-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 equieffective 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 5 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.
麻醉剂可增强中枢神经系统中γ-氨基丁酸（GABA）介导的抑制作用。已表明不同药物对紧张性与突触性GABA受体的作用程度不同，但不同形式的突触抑制是否也有不同程度的参与仍不清楚。考虑到这一点，我们检验了不同类型的GABA介导的突触表现出不同麻醉敏感性这一假设。本研究比较了异氟烷、氟烷、戊巴比妥、硫喷妥钠和丙泊酚对双脉冲GABAA受体介导的突触抑制的影响。还研究了对谷氨酸介导的易化作用的影响。
在大鼠海马脑片中测量突触反应。采用顺向双脉冲刺激来评估麻醉剂对CA1神经元谷氨酸介导的兴奋性输入或GABA介导的抑制性输入的影响。采用逆向刺激来评估麻醉剂对CA1背景兴奋性的影响。在使群体峰电位抑制达到等效浓度的情况下研究药物，以比较它们对突触抑制的相对作用程度。
对兴奋性谷氨酸突触处双脉冲易化的麻醉作用程度不同很明显，阻断GABA抑制揭示了戊巴比妥以前未被发现的突触前作用。虽然所有5种麻醉剂都抑制了CA1神经元的突触诱发兴奋，但药物之间GABA介导的抑制增强的参与情况有很大差异。丙泊酚、硫喷妥钠和戊巴比妥增强了单脉冲抑制，但氟烷和异氟烷只是轻微增强。相反，异氟烷强烈增强了双脉冲抑制，硫喷妥钠也是如此，但丙泊酚、戊巴比妥和氟烷的效果较差。
这些观察结果支持这样的观点，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敏感性有助于解释不同类麻醉剂产生的独特行为/临床特征，并表明存在新药物开发的选择性靶点。
