Characterization of Novel Neural Respiratory Circuit to Counter Opioid-Induced Respiratory Depression

项目摘要 我们已经确定了一个新的性质的颈脊髓，调节呼吸活动，无论是速度 和呼吸深度，这样在小鼠和人类中阿片类药物抑制状态下的呼吸驱动 在脊髓硬膜外刺激期间增加。硬膜外刺激后呼吸频率增加， 特定颈髓位置时有自主呼吸，且有节奏的呼吸可 当呼吸状态被抑制并且没有自主呼吸时产生。这是一个重要 因为脑干，其中包含节奏产生中心的呼吸，是一个困难的观察， 手术和治疗通道区域。如果手术可触及其他神经区域（即硬膜外 刺激）或非侵入性手段（即经皮刺激），例如在颈椎中， 影响呼吸或包含自己的节奏呼吸元素，这些可能代表潜在的 治疗目标是逆转阿片类药物引起的呼吸抑制。因此，我们提出了一项战略， 描述这种新型颈部呼吸回路。首先，我们将进行广泛的电子测绘， 通过机器学习策略辅助小鼠颈脊髓的呼吸反应元件，以及 我们将描述这种反应的机制基础，即与阿片受体和呼吸系统的关系 反应，并使用光遗传学技术鉴定负责呼吸反应的神经元。指导 通过动物实验，我们将进一步确定人类颈部呼吸反应位点。三是 使所鉴定的呼吸活性区经受增加剂量的阿片样物质以进一步表征所述呼吸活性区， 这些区域的剂量反应曲线。第四，我们将评估这种翻译的可行性和实用性。 脊髓移植患者阿片类药物引起呼吸抑制逆转策略 刺激物。这些研究将提供一个解剖和电生理特性的， 呼吸回路内的颈椎，并提供实用的信息，为治疗阿片类药物引起的 呼吸抑制所获得的结果，特别是因为它们是在人类中获得的，将具有 对我们理解呼吸回路的直接转化影响，反过来可能会防止死亡 因为阿片类药物过量

PROJECT SUMMARY We have identified a novel property of the cervical spinal cord that modulates respiratory activity, both the rate and depth of breathing, such that the respiratory drive in opioid-suppressed states in mice and humans increases during spinal cord epidural stimulation. Respiratory rates are increased upon epidural stimulation of specific cervical spinal cord locations when there is spontaneous breathing, and rhythmic breathing can be generated when the respiratory state is depressed and spontaneous breathing is absent. This is an important observation because the brainstem, which contains the rhythm-generating center for respiration, is a difficult area for surgical and therapeutic access. If there are other accessible neural regions by surgery (i.e. epidural stimulation) or non-invasive means (i.e. transcutaneous stimulation), for example in the cervical spine, that influence respiration or contain their own rhythmic respiratory elements, these may represent potential therapeutic targets to reverse opioid-induced respiratory depression. Thus, we have proposed a strategy to characterize this novel cervical respiratory circuit. First, we will conduct extensive electrical mapping of the respiratory responsive elements of the cervical spinal cord in mice aided by machine learning strategies, and we will characterize the mechanistic basis for this response, the relation to opioid receptors to the respiratory response, and identity neurons responsible for the respiratory response using optogenetic techniques. Guided by the animal studies, we will then confirm the cervical respiratory responsive loci in humans. Third, we will subject the identified respiratory competent regions to increasing doses of opioid to further characterize the dose-response profile of these regions. Fourth, we will assess the feasibility and practical translation of this strategy to reverse opioid-induced respiratory depression in three patients implanted with spinal cord stimulators. These studies will provide an anatomical and electrophysiological characterization of the respiratory circuit within the cervical spine and provide practical information for the treatment of opioid-induced respiratory depression. The results obtained, especially because they are obtained in humans, will have an immediate translational impact on our understanding of the respiratory circuit that may, in turn, prevent deaths due to opioid overdose.