Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101.
Departments of Pediatrics, University of Washington, Seattle, Washington 98195.
J Neurosci. 2021 Dec 1;41(48):9919-9931. doi: 10.1523/JNEUROSCI.1329-21.2021. Epub 2021 Oct 25.
Death from opioid overdose is typically caused by opioid-induced respiratory depression (OIRD). A particularly dangerous characteristic of OIRD is its apparent unpredictability. The respiratory consequences of opioids can be surprisingly inconsistent, even within the same individual. Despite significant clinical implications, most studies have focused on average dose-r esponses rather than individual variation, and there remains little insight into the etiology of this apparent unpredictability. The preBötzinger complex (preBötC) in the ventral medulla is an important site for generating the respiratory rhythm and OIRD. Here, using male and female C57-Bl6 mice , we demonstrate that the preBötC can assume different network states depending on the excitability of the preBötC and the intrinsic membrane properties of preBötC neurons. These network states predict the functional consequences of opioids in the preBötC, and depending on network state, respiratory rhythmogenesis can be either stabilized or suppressed by opioids. We hypothesize that the dynamic nature of preBötC rhythmogenic properties, required to endow breathing with remarkable flexibility, also plays a key role in the dangerous unpredictability of OIRD. Opioids can cause unpredictable, life-threatening suppression of breathing. This apparent unpredictability makes clinical management of opioids difficult while also making it challenging to define the underlying mechanisms of OIRD. Here, we find in brainstem slices that the preBötC, an opioid-sensitive subregion of the brainstem, has an optimal configuration of cellular and network properties that results in a maximally stable breathing rhythm. These properties are dynamic, and the state of each individual preBötC network relative to the optimal configuration of the network predicts how vulnerable rhythmogenesis is to the effects of opioids. These insights establish a framework for understanding how endogenous and exogenous modulation of the rhythmogenic state of the preBötC can increase or decrease the risk of OIRD.
阿片类药物过量导致的死亡通常是由阿片类药物引起的呼吸抑制（OIRD）引起的。OIRD 的一个特别危险的特征是其明显的不可预测性。即使在同一个人身上，阿片类药物的呼吸后果也可能出人意料地不一致。尽管具有重要的临床意义，但大多数研究都集中在平均剂量反应上，而不是个体差异上，对于这种明显的不可预测性的病因仍知之甚少。腹侧脑桥的 PreBötzinger 复合体（preBötC）是产生呼吸节律和 OIRD 的重要部位。在这里，我们使用雄性和雌性 C57-Bl6 小鼠证明，preBötC 可以根据 preBötC 的兴奋性和 preBötC 神经元的内在膜特性呈现出不同的网络状态。这些网络状态预测了阿片类药物在 preBötC 中的功能后果，并且根据网络状态，呼吸节律发生可以被阿片类药物稳定或抑制。我们假设，赋予呼吸显著灵活性所需的 preBötC 节律发生特性的动态性质，在 OIRD 的危险不可预测性中也起着关键作用。阿片类药物会导致呼吸不可预测、危及生命的抑制。这种明显的不可预测性使得阿片类药物的临床管理变得困难，同时也使得定义 OIRD 的潜在机制具有挑战性。在这里，我们在脑片上发现，preBötC 是脑干的一个阿片类药物敏感亚区，具有导致呼吸节律最大稳定的细胞和网络特性的最佳配置。这些特性是动态的，每个个体 preBötC 网络相对于网络的最佳配置的状态预测节律发生对阿片类药物的影响的脆弱性。这些见解为理解内源性和外源性调制 preBötC 的节律发生状态如何增加或降低 OIRD 的风险奠定了基础。
