Mechanisms of repeated opioid use dependent remodeling in respiratory control

项目总结 与合成阿片类药物有关的过量死亡人数在过去20年中增加了6倍。反复使用阿片类药物 使用者，如患有物质使用障碍的个人，是阿片类药物诱导的最大风险 呼吸抑制，过量用药的标志。虽然对蜂窝、电路和 阿片类药物抑制呼吸存在的药理学基础，重复使用阿片类药物如何影响控制 对呼吸的研究在很大程度上是不够的。尽管临床和实验室证据表明 反复使用阿片类药物显著改变了呼吸的控制。这种知识鸿沟导致了有限的 解决阿片类药物重复使用者中阿片类药物过量问题的能力--阿片类药物最易过量的人群 死亡。即使在反复使用阿片类药物的人中，对阿片类药物引起的呼吸抑制的耐受性也可能不稳定。它是 众所周知，对阿片类药物的止痛和兴奋作用的耐受性具有上下文依赖性。 同样，阿片类药物过量的敏感性也会受到这些药物使用环境的影响。 然而，上下文依赖机制对阿片类药物诱导的呼吸易感性的贡献 抑郁症是未知的。我们开发了一种反复使用芬太尼导致呼吸变化的模型 与反复使用阿片类药物的呼吸表型一致--包括一种耐受性 依赖于上下文。这项提案的主要目标是审查涉及到的机制 重复阿片类药物使用依赖呼吸控制的重塑。我们假设反复使用阿片类药物 通过呼吸网络中的直接细胞变化和通过 一种不稳定形式的耐受性的出现依赖于行为条件反射和神经调节 呼吸系统。这项工作将检查：(1)细胞和神经生理机制 反复使用阿片类药物后呼吸控制的重塑；(2)习得行为的贡献 在产生状态依赖性呼吸和影响阿片类药物敏感性方面有作用；以及(3) 神经调节在影响反复使用阿片类药物前后吸气驱动的稳定性中起作用。因此， 这项工作为理解阿片类药物重复使用改良器提供了一个亟需的机制框架 对呼吸的控制。这样的框架可以作为新的方法和疗法的基础 应对最容易服药过量的个人的阿片类药物过量风险--死亡和与呼吸相关 并存疾病。

PROJECT SUMMARY Overdose deaths related to synthetic opioids have increased six-fold over the past 20 years. Repeated opioid users, such as individuals suffering from substance use disorder, are at the greatest risk for opioid induced respiratory depression, the hallmark of overdose. Although extensive understanding into the cellular, circuit and pharmacological basis by which opioids suppress breathing exists, how repeated opioid use impacts the control of breathing has been largely understudied. This is despite the clinical and laboratory evidence indicating that repeated opioid use significantly changes the control of breathing. This knowledge gap contributes to the limited ability to address opioid overdose among repeat opioid users—the population most vulnerable to overdose death. Even among repeat opioid users, tolerance to opioid induced respiratory depression can be labile. It is well-recognized that tolerance to the analgesic and euphoric effects of opioids has context-dependence. Similarly, the susceptibility to opioid overdose can be influenced by the context in which these drugs are used. Yet, the contribution of context-dependent mechanisms to the susceptibility of opioid induced respiratory depression is unknown. We developed a model of repeated fentanyl use that produces changes in breathing consistent with the breathing phenotype observed in repeated opioid users—including a form of tolerance dependent on context. The primary objective of this proposal is to examine the mechanisms involved with repeated opioid use-dependent remodeling in the control of breathing. We hypothesize that repeated opioid use remodels the control of breathing through direct cellular changes in the respiratory network and through the emergence of a labile form of tolerance dependent on behavioral conditioning and neuromodulation within the respiratory network. This work will examine: (1) the cellular and the neurophysiological mechanisms that underlie the remodeling of the control of breathing after repeated opioid use; (2) the contribution that learned behavior has in producing state-dependent breathing and influencing opioid susceptibility; and (3) the role that neuromodulation plays in influencing the stability of inspiratory drive prior to and after repeated opioid use. Thus, this work provides a much-needed mechanistic framework for understanding how repeated opioid use remodels the control of breathing. Such a framework can serve as a foundation for novel approaches and therapies to address the risk of opioid overdose in individuals most vulnerable to overdose-death and respiratory-associated co-morbidities.