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

项目总结 我们已经确定了颈髓的一种新特性，它调节呼吸活动，既有 以及呼吸深度，从而使小鼠和人类处于阿片类药物抑制状态的呼吸驱动 脊髓硬膜外刺激时增加。硬膜外刺激时呼吸频率增加 当有自主呼吸时，特定的颈髓位置，以及有节奏的呼吸可以 当呼吸状态处于压抑状态且没有自主呼吸时产生。这是一个重要的 观察是因为包含呼吸节律产生中心的脑干是一个困难的 手术和治疗通道区域。如果有其他可通过手术到达的神经区(即硬膜外 刺激)或非侵入性手段(即经皮刺激)，例如在颈椎中， 影响呼吸或包含自身有节奏的呼吸元素，这些可能代表潜在的 逆转阿片类药物引起的呼吸抑制的治疗靶点。因此，我们提出了一项战略，以 描述这种新颖的颈部呼吸回路。首先，我们将进行广泛的电子测绘 机器学习策略辅助的小鼠颈脊髓呼吸反应元件，以及 我们将描述这种反应的机制基础，即阿片受体与呼吸的关系。 利用光遗传技术识别负责呼吸反应的神经元。引导式 通过动物研究，我们将确认人类颈部的呼吸反应位点。第三，我们将 使已识别的呼吸适能区域接受更大剂量的阿片类药物，以进一步表征 这些区域的剂量-反应曲线。第四，我们将评估这本书的可行性和实用翻译 3例脊髓植入患者逆转阿片类药物所致呼吸抑制的策略 刺激器。这些研究将提供一个解剖和电生理特征的 为治疗阿片类药物所致颈椎内呼吸循环障碍提供实用信息 呼吸抑制。所获得的结果，特别是因为它们是在人类身上获得的，将会有一个 对我们对呼吸回路的理解产生直接的翻译影响，这可能反过来防止死亡 由于阿片类药物过量。

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.