Redesigning General Anesthesia

描述（由申请人提供）：全身麻醉是一种可逆的、药物引起的行为状态，包括无意识、健忘症、镇痛和不动，具有重要生理系统的稳定和控制。这一现代医学的基本工具对于允许成千上万的患者每天安全地接受大多数手术和许多非手术治疗至关重要。今天，这种状态是通过在大脑和中枢神经系统的多个部位施用多种药物来诱导和维持的。全麻苏醒是一个被动的过程，麻醉药物仅在手术结束时停止使用，没有药物主动逆转其作用。允许多种药物在多个部位起作用而没有特定机制终止其作用最有可能解释麻醉相关发病率的重要组成部分；药物副作用（恶心、低血压、呼吸抑制、体温过低）是由于作用于预期靶点以外的部位，而持续效应（谵妄、认知功能障碍）是由于作用于预期靶点的时间比预期的长。因此，目前生产的全身麻醉是高度非特异性和低效的。尽管麻醉学在现代医疗保健中发挥着核心作用，但该领域的研究过于关注于破译当前药物的麻醉和毒性机制，而很少或根本没有注意到开发新方法。这个范式转换问题的答案将彻底改变麻醉学，而不是“目前的麻醉药是如何工作的？”，而是“全身麻醉的状态应该如何设计？”我们假设答案是通过开发策略来直接控制大脑的自然抑制途径和唤醒中心。我们建议在啮齿类动物模型中结合光遗传、电和药理学操作来重新设计全身麻醉，通过精确定时控制大脑的自然抑制通路及其唤醒中心来创造这种行为状态。如果成功，这项研究将为大脑觉醒控制提供一个新的基本理解，并最终提供新的麻醉学实践，包括：神经生理学设计的方法来创造全身麻醉；降低发病率；改善脑功能监测；非麻醉医师更安全的麻醉护理；可能还会有治疗抑郁症、失眠、疼痛和昏迷等觉醒障碍的新疗法。

DESCRIPTION (provided by applicant): General anesthesia is a reversible, drug-induced behavioral state comprised of unconsciousness, amnesia, analgesia and immobility with stability and control of vital physiological systems. This fundamental tool of modern medicine is crucial for allowing thousands of patients daily to safely undergo most surgical and many non-surgical procedures. Today this state is induced and maintained by administering multiple drugs that act at multiple sites in the brain and central nervous system. Emergence from general anesthesia is a passive process whereby anesthetic drugs are merely discontinued at the end of surgery and no drugs are administered to actively reverse their effects. Allowing multiple drugs to act at multiple sites without specific mechanisms to terminate their effects most likely explains a significant component of anesthesia-related morbidity; drug side effects (nausea, hypotension, respiratory depression, hypothermia) are due to actions at sites other than their intended targets whereas persistent effects (delirium, cognitive dysfunction) are due to actions at intended targets for periods longer than desired. Hence, general anesthesia, as presently produced, is highly non-specific and inefficient. Despite the central role of anesthesiology in modern healthcare, research in this field is overly focused on deciphering the anesthetic and toxic mechanisms of current drugs with little to no attention being paid to developing new approaches. The paradigm-shifting question whose answer will revolutionize anesthesiology is not, "how do current anesthetics work?", but rather, "how should the state of general anesthesia be designed?" We hypothesize that the answer is by developing strategies to control directly the brain's natural inhibitory pathways and arousal centers. We propose to redesign general anesthesia by combining optogenetic, electrical and pharmacological manipulations in rodent models to create this behavioral state through precisely timed control of the brain's natural inhibitory pathways and its arousal centers. If successful this research will provide a new fundamental understanding of brain arousal control, and eventually, new anesthesiology practices including: neurophysiologically-designed approaches to creating general anesthesia; reduction in morbidity; improved brain function monitoring; safer anesthesia care by non-anesthesiologists; and possibly novel therapies for arousal disorders such as depression, insomnia, pain and coma.