Mechanisms of repeated opioid use dependent remodeling in respiratory control

呼吸控制中阿片类药物重复使用依赖性重塑的机制

• 批准号: 10677776
• 负责人: Alfredo J Garcia
• 金额: $ 67.09万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677776
• 关键词: Acute; Address; Analgesics; Association Learning; Automobile Driving; Behavioral; Blood gas; Brain Stem; Breathing; Cause of Death; Clinical; Collaborations; Dependence; Drug usage; Electrophysiology (science); Failure; Fentanyl; Fiber; Foundations; Genetic; Healthcare Systems; Homeostasis; In Vitro; Individual; Ischemia; Knowledge; Laboratories; Learning; Machine Learning; Metabolism; Modeling; Morbidity - disease rate; Neurobiology; Opioid; Outcome; Overdose; Pattern; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Photometry; Physicians; Physiological; Play; Population; Predisposition; Prevention strategy; Property; Reflex action; Reperfusion Therapy; Research; Research Personnel; Risk; Role; Scientist; Stimulus; Substance Use Disorder; Synapses; Testing; United States; Ventilatory Depression; Whole Body Plethysmography; Work; comorbidity; conditioning; experience; fentanyl use; genetic approach; in vivo; learned behavior; neural network; neuropathology; neurophysiology; neuroregulation; noradrenergic; novel strategies; novel therapeutics; opioid epidemic; opioid mortality; opioid overdose; opioid use; opioid use disorder; opioid user; overdose death; overdose prevention; pharmacologic; respiratory; response; synthetic opioid; transcriptomic profiling

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.

项目概要 过去 20 年来，与合成阿片类药物相关的过量死亡增加了六倍。 使用者，例如患有药物滥用障碍的个人，阿片类药物诱导的风险最大 尽管对细胞、回路和机制有广泛的了解，但呼吸抑制是药物过量的标志。 阿片类药物抑制呼吸的药理学基础，重复使用阿片类药物如何影响控制 尽管临床和实验室证据表明，呼吸的作用尚未得到充分研究。 重复使用阿片类药物会显着改变呼吸控制。 能够解决重复阿片类药物使用者（最容易过量服用阿片类药物的人群）中阿片类药物过量的问题 即使重复使用阿片类药物，对阿片类药物引起的呼吸抑制的耐受性也不稳定。 众所周知，对阿片类药物的镇痛和欣快作用的耐受性具有情境依赖性。 同样，阿片类药物过量的易感性可能受到这些药物使用环境的影响。 然而，环境依赖性机制对阿片类药物诱导的呼吸系统易感性的贡献 我们开发了一种重复使用芬太尼的模型，该模型会产生呼吸变化。 与重复阿片类药物使用者观察到的呼吸表型一致——包括某种形式的耐受性 该提案的主要目标是研究相关机制。 重复使用阿片类药物依赖于呼吸控制的重塑我们勇敢地重复使用阿片类药物。 通过呼吸网络中的直接细胞变化以及通过 依赖于行为调节和神经调节的不稳定耐受形式的出现 这项工作将研究：（1）潜在的细胞和神经生理机制。 重复使用阿片类药物后呼吸控制的重塑（2）习得行为的贡献； [0103] 在产生状态依赖性呼吸和影响阿片类药物敏感性方面具有的作用； 神经调节在重复使用阿片类药物之前和之后影响吸气驱动的稳定性。 这项工作为理解阿片类药物的重复使用如何重塑提供了一个急需的机制框架 这样的框架可以作为新方法和疗法的基础。 解决最容易发生药物过量死亡和呼吸道相关疾病的个人服用阿片类药物过量的风险 合并症。