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Propofol differentially induces unconsciousness and respiratory depression through distinct interactions between GABAA receptor and GABAergic neuron in corresponding nuclei
Acta Biochimica et Biophysica Sinica ( IF 3.7 ) Pub Date : 2021-06-17 , DOI: 10.1093/abbs/gmab084
Junli Jiang 1, 2 , Yingfu Jiao 1 , Po Gao 1 , Wen Yin 1 , Wei Zhou 1 , Yunchun Zhang 1 , Yanjun Liu 3 , Daxiang Wen 1 , Yuan Wang 2 , Liang Zhou 2 , Tian Yu 2, 4 , Weifeng Yu 1
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Propofol is the most commonly used intravenous anesthetic worldwide. It can induce loss of consciousness prior to the occurrence of severe respiratory suppression, which is also a pharmacodynamic feature of all general anesthetics. However, the neural mechanisms underlying this natural phenomenon are controversial and highly related to patient safety. In the present study, we demonstrated that the pharmacodynamic effects of propofol (50 and 100 μM) on suppression of consciousness-related excitatory postsynaptic currents in the medial prefrontal cortex (mPFC) and centromedian nucleus of the thalamus (CMT) were lower than those in the kernel respiratory rhythmogenesis nucleus pre-Bötzinger complex (PrBo). Furthermore, we unexpectedly found that the GABAA receptor β3 subunit is the key target for propofol’s action and that it is mutually and exclusively expressed in GABAergic neurons. It is also more abundant in the mPFC and CMT, but mainly co-localized with GABAergic neurons in the PrBo. As a result, the differentiated expression pattern should mediate more neuron suppression through the activation of GABAergic neurons in the mPFC and CMT at low doses of propofol (50 μM). However, PrBo GABAergic neurons were only activated by propofol at a high dose (100 μM). These results highlight the detailed pharmacodynamic effects of propofol on consciousness-related and respiration-related nuclei and provide the distinct interaction mechanism between the β3 subunit and GABAergic neurons in mediating the suppression of consciousness compared to the inhibition of respiration.

中文翻译:

丙泊酚通过 GABAA 受体和相应细胞核中 GABA 能神经元之间的不同相互作用,不同程度地诱导无意识和呼吸抑制

丙泊酚是全世界最常用的静脉麻醉剂。它可以在发生严重呼吸抑制之前引起意识丧失,这也是所有全身麻醉药的药效学特征。然而,这种自然现象背后的神经机制存在争议,并且与患者安全高度相关。在本研究中,我们证明了丙泊酚(50 和 100 μM)抑制内侧前额叶皮层 (mPFC) 和丘脑着丝核 (CMT) 中与意识相关的兴奋性突触后电流的药效学作用低于核呼吸节律核前 Bötzinger 复合体 (PrBo)。此外,我们意外地发现 GABA A受体 β3 亚基是丙泊酚作用的关键靶标,它在 GABA 能神经元中相互唯一表达。它在 mPFC 和 CMT 中也更丰富,但主要与 PrBo 中的 GABA 能神经元共定位。因此,分化的表达模式应该通过在低剂量丙泊酚 (50 μM) 下激活 mPFC 和 CMT 中的 GABA 能神经元来介导更多的神经元抑制。然而,PrBo GABA 能神经元仅被高剂量(100 μM)的丙泊酚激活。这些结果突出了丙泊酚对意识相关和呼吸相关核的详细药效学作用,并提供了 β3 亚基和 GABA 能神经元之间在介导意识抑制与呼吸抑制方面的独特相互作用机制。
更新日期:2021-07-28
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