Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143;
Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143.
Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):E10740-E10747. doi: 10.1073/pnas.1808622115. Epub 2018 Oct 22.
Orexin (also known as hypocretin) neurons in the hypothalamus play an essential role in sleep-wake control, feeding, reward, and energy homeostasis. The likelihood of anesthesia and sleep sharing common pathways notwithstanding, it is important to understand the processes underlying emergence from anesthesia. In this study, we investigated the role of the orexin system in anesthesia emergence, by specifically activating orexin neurons utilizing the designer receptors exclusively activated by designer drugs (DREADD) chemogenetic approach. With injection of adeno-associated virus into the orexin-Cre transgenic mouse brain, we expressed the DREADD receptor hM3Dq specifically in orexin neurons and applied the hM3Dq ligand clozapine to activate orexin neurons. We monitored orexin neuronal activities by c-Fos staining and whole-cell patch-clamp recording and examined the consequence of orexin neuronal activation via EEG recording. Our results revealed that the orexin-DREADD mice with activated orexin neurons emerged from anesthesia with significantly shorter latency than the control mice. As an indication of reduced pain sensitivity, these orexin-DREADD mice took longer to respond to the 55 °C thermal stimuli in the hot plate test and exhibited significantly less frequent licking of the formalin-injected paw in the formalin test. Our study suggests that approaches to activate the orexin system can be beneficial in postoperative recovery.
下丘脑的食欲素（也称为下丘脑分泌素）神经元在睡眠-觉醒控制、摄食、奖励和能量稳态中发挥着重要作用。尽管麻醉和睡眠可能共享共同的途径，但了解麻醉苏醒的背后过程很重要。在这项研究中，我们通过特异性激活食欲素神经元来研究食欲素系统在麻醉苏醒中的作用，具体方法是利用专门被设计药物激活的受体（DREADD）化学遗传方法。通过将腺相关病毒注射到食欲素-Cre 转基因小鼠的大脑中，我们在食欲素神经元中特异性表达了 DREADD 受体 hM3Dq，并应用 hM3Dq 配体氯氮平激活食欲素神经元。我们通过 c-Fos 染色和全细胞膜片钳记录监测食欲素神经元的活动，并通过 EEG 记录检查食欲素神经元激活的后果。我们的结果表明，与对照小鼠相比，激活食欲素神经元的食欲素-DREADD 小鼠从麻醉中苏醒的潜伏期明显缩短。作为疼痛敏感性降低的一个迹象，这些食欲素-DREADD 小鼠在热板测试中对 55°C 的热刺激的反应时间更长，在福尔马林注射的爪子中舔的频率明显减少。我们的研究表明，激活食欲素系统的方法可能有益于术后恢复。
