An essential role for orexins in emergence from general anesthesia
An essential role for orexins in emergence from general anesthesia
复制标题
DOI：
10.1073/pnas.0707146105
复制
发表时间：
2008-01-29
影响因子：
11.1
通讯作者：
Yanagisawa, Masashi
中科院分区：
文献类型：
--
作者：
Kelz, Max B.;Sun, Yi;Yanagisawa, Masashi
麻醉状态产生和消散的神经机制仍然未知。一种普遍的观点是，从麻醉中苏醒是诱导的逆过程，是通过消除麻醉药物从中枢神经系统作用部位而实现的。麻醉引起的意识丧失可能是由于麻醉剂与调节睡眠和觉醒的神经回路的特定相互作用造成的。食欲素能激动剂和拮抗剂有可能改变麻醉状态的稳定性。在本报告中，我们完善了内源性食欲素系统在影响从麻醉状态苏醒（但不影响进入麻醉状态）方面的作用，并在此过程中，我们区分了诱导机制和苏醒机制。我们证明异氟烷和七氟烷这两种常用的全身麻醉剂可抑制食欲素能神经元中的 c-Fos 表达，但不会抑制邻近的黑色素浓缩激素 (MCH) 神经元的表达。表明唤醒活性的食欲素能神经元受到这些麻醉剂的抑制。食欲素能神经元的基因消融会导致获得性小鼠发作性睡病，从而延迟麻醉苏醒，而不会改变麻醉诱导。选择性食欲素 1 受体拮抗剂的药理学研究证实，食欲素对麻醉苏醒有特定作用，且诱导过程没有相关变化。我们的结论是，介导诱导和出现的神经基质存在重要差异。这些发现支持这样的概念：苏醒部分取决于大脑清醒活跃区域的募集和稳定。
The neural mechanisms through which the state of anesthesia arises and dissipates remain unknown. One common belief is that emergence from anesthesia is the inverse process of induction, brought about by elimination of anesthetic drugs from their CNS site(s) of action. Anesthetic-induced unconsciousness may result from specific interactions of anesthetics with the neural circuits regulating sleep and wakefulness. Orexinergic agonists and antagonists have the potential to alter the stability of the anesthetized state. In this report, we refine the role of the endogenous orexin system in impacting emergence from, but not entry into the anesthetized state, and in doing so, we distinguish mechanisms of induction from those of emergence. We demonstrate that isoflurane and sevoflurane, two commonly used general anesthetics, inhibit c-Fos expression in orexinergic but not adjacent melanin-concentrating hormone (MCH) neurons; suggesting that wake-active orexinergic neurons are inhibited by these anesthetics. Genetic ablation of orexinergic neurons, which causes acquired murine narcolepsy, delays emergence from anesthesia, without changing anesthetic induction. Pharmacologic studies with a selective orexin-1 receptor antagonist confirm a specific orexin effect on anesthetic emergence without an associated change in induction. We conclude that there are important differences in the neural substrates mediating induction and emergence. These findings support the concept that emergence depends, in part, on recruitment and stabilization of wake-active regions of brain.