Designer receptor manipulations reveal a role of the locus coeruleus noradrenergic system in isoflurane general anesthesia
Designer receptor manipulations reveal a role of the locus coeruleus noradrenergic system in isoflurane general anesthesia
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DOI：
10.1073/pnas.1310025111
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发表时间：
2014-03-11
影响因子：
11.1
通讯作者：
Aston-Jones, Gary
中科院分区：
文献类型：
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作者：
Vazey, Elena M.;Aston-Jones, Gary
推动全身麻醉苏醒的机制还不是很清楚。去甲肾上腺素能脑蓝斑(LC)调节觉醒，可能对全身麻醉状态有影响。利用病毒传递的设计者受体特异性地控制LC去甲肾上腺素(NE)神经元，我们研究了异氟醚麻醉下LC-NE活性与全身麻醉状态之间的因果关系。在异氟醚持续深麻醉下，选择性激活LC-NE神经元产生皮层脑电(EEG)激活。具体地说，激活LC-NE降低了EEG中的爆发抑制，并使峰值EEG频率右移，同时降低了增量EEG功率，增加了增量EEG功率。脑电功率，大脑皮层觉醒的测量。激活LC-NE也加速了异氟醚深度麻醉的行为苏醒；这可被β或α1去甲肾上腺素能拮抗剂阻止。此外，仅这些肾上腺素受体拮抗剂就足以显著延长中枢或外周给药的麻醉持续时间。激活LC-NE也可延缓麻醉诱导。我们的结果表明LC-NE系统对麻醉状态有很强的调节作用，LC-NE神经递质的改变单独影响异氟醚全麻苏醒。综上所述，这些发现扩大了我们对全身麻醉和皮质唤醒机制的理解，并对优化全身麻醉的临床安全性和管理具有重要意义。
Mechanisms driving emergence from general anesthesia are not well understood. The noradrenergic brain nucleus locus coeruleus (LC) modulates arousal and may have effects on general anesthetic state. Using virally delivered designer receptors to specifically control LC norepinephrine (NE) neurons, we investigated the causal relationship between LC-NE activity and general anesthetic state under isoflurane. Selective activation of LC-NE neurons produced cortical electroencephalography (EEG) activation under continuous deep isoflurane anesthesia. Specifically, LC-NE activation reduced burst suppression in EEG and drove a rightward shift in peak EEG frequency with reduced delta EEG power and increased. EEG power, measures of cortical arousal. LC-NE activation also accelerated behavioral emergence from deep isoflurane anesthesia; this was prevented with beta or alpha 1 noradrenergic antagonists. Moreover, these adrenoreceptor antagonists alone were sufficient to markedly potentiate anesthetic duration when delivered centrally or peripherally. Induction of anesthesia also was retarded by LC-NE activation. Our results demonstrate that the LC-NE system strongly modulates the anesthetic state, and that changes in LC-NE neurotransmission alone can affect the emergence from isoflurane general anesthesia. Taken together, these findings extend our understanding of mechanisms underlying general anesthesia and cortical arousal, and have significant implications for optimizing the clinical safety and management of general anesthesia.