Sevoflurane depresses neurons in the medial parabrachial nucleus by potentiating postsynaptic GABA A receptors and background potassium channels
Sevoflurane depresses neurons in the medial parabrachial nucleus by potentiating postsynaptic GABA A receptors and background potassium channels
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七氟烷通过突触后 GABAA 受体和背景钾通道抑制内侧臂旁核神经元
DOI：
10.1016/j.neuropharm.2020.108249
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发表时间：
2020-12-15
影响因子：
4.7
通讯作者：
Huang, Zhi-Li
中科院分区：
文献类型：
--
作者：
Xu, Wei;Wang, Lu;Huang, Zhi-Li
尽管临床上持续使用了170多年，但全麻产生催眠的神经元机制仍不清楚。以往的研究表明，麻醉药通过作用于内源性唤醒电路来发挥催眠作用。最近，研究表明内侧臂旁核（MPB）是脑桥背外侧一个新的促醒成分。然而，目前尚不清楚MPB是否以及如何促进麻醉诱导催眠。在这里，我们研究了七氟醚（一种广泛使用的挥发性麻醉剂，最能代表卤化醚类药物）对小鼠MPB神经元的作用。使用体内纤维光度法，我们发现在七氟醚诱导的意识丧失期间，MPB神经元的种群活动受到抑制。通过体外全细胞膜片钳记录，我们发现七氟醚以浓度依赖和可逆的方式抑制MPB神经元的放电速率。在与催眠浓度相当的浓度下，七氟醚增强突触GABA(a)受体（GABA(a)-Rs），七氟醚对MPB神经元放电速率的抑制作用被选择性GABA(a)-R拮抗剂微螺毒素完全消除。在相当于静止MAC的浓度下，七氟醚直接超极化MPB神经元，并通过增加基础钾电导导致膜输入电阻显著降低。此外，在催眠的MAC阶段，七氟醚吸入对MPB中GABA(A)-Rs的药物阻断延长了诱导时间，缩短了苏醒时间。这些结果表明，七氟醚通过突触后GABA -Rs和背景钾通道抑制MPB神经元，这有助于七氟醚诱导催眠。
Despite persistent clinical use for over 170 years, the neuronal mechanisms by which general anesthetics produce hypnosis remain unclear. Previous studies suggest that anesthetics exert hypnotic effects by acting on endogenous arousal circuits. Recently, it has been shown that the medial parabrachial nucleus (MPB) is a novel wakepromoting component in the dorsolateral pons. However, it is not known whether and how the MPB contributes to anesthetic-induced hypnosis. Here, we investigated the action of sevoflurane, a widely used volatile anesthetic agent that best represents the drug class of halogenated ethers, on MPB neurons in mice. Using in vivo fiber photometry, we found that the population activities of MPB neurons were inhibited during sevoflurane-induced loss of consciousness. Using in vitro whole-cell patch-clamp recordings, we revealed that sevoflurane suppressed the firing rate of MPB neurons in concentration-dependent and reversible manners. At a concentration equal to MAC of hypnosis, sevoflurane potentiated synaptic GABA(A) receptors (GABA(A)-Rs), and the inhibitory effect of sevoflurane on the firing rate of MPB neurons was completely abolished by picrotoxin, which is a selective GABA(A)-R antagonist. At a concentration equivalent to MAC of immobility, sevoflurane directly hyperpolarized MPB neurons and induced a significant decrease in membrane input resistance by increasing a basal potassium conductance. Moreover, pharmacological blockade of GABA(A)-Rs in the MPB prolongs induction and shortens emergence under sevoflurane inhalation at MAC of hypnosis. These results indicate that sevoflurane inhibits MPB neurons through postsynaptic GABA(A)-Rs and background potassium channels, which contributes to sevofluraneinduced hypnosis.