Divergent ventilatory responses during opioid-induced respiratory depression in response to repeated fentanyl use.

IF 3.6 2区 医学 Q1 PHYSIOLOGY
Karan G Rai, Chinwendu U Nwakudu, Caroline C Szujewski, Brigitte M Browe, Gia E Fisher, Willard W Sharp, Andrew K Tryba, Alfredo J Garcia
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引用次数: 0

Abstract

Opioid-induced respiratory depression (OIRD) is the hallmark of opioid overdose and a major risk factor for death due to fentanyl use. Although repeat opioid use (ROU) elevates the risk of death, understanding its influence over breathing and its control has been poorly resolved. We developed a mouse model of recurrent fentanyl use over 5 days to examine how ROU impacts breathing and activity from the pre-Bötzinger complex (preBötC), the brainstem network driving inspiratory rhythmogenesis. Initial fentanyl use caused a profound metabolic crisis during OIRD involving a mismatch between ventilation and oxygen consumption. By day 5 of ROU, 77% of mice exhibited an adaptive ventilatory response following ROU, which was accompanied by an improved relationship between ventilation and oxygen consumption during OIRD. However, in the remaining minority, the adaptive response during OIRD failed to emerge following ROU. This divergence emphasizes the heterogeneity in ventilatory and metabolic outcomes following ROU. Moreover, following ROU, rhythmogenesis in the preBötzinger complex was less sensitive to mu-opioid receptor agonism, indicating that adaptation to ROU involves centrally mediated changes in this brainstem network. These findings reveal a series of physiological changes following ROU, typically resulting in improved ventilation and oxygenation during OIRD. Such changes, or lack of thereof, may contribute to the unpredictable nature of overdose susceptibility among opioid users.NEW & NOTEWORTHY Recurring fentanyl use is a significant factor contributing to opioid-related deaths, yet the physiological impact of repeat opioid use on breathing remains poorly understood. This study demonstrates that divergent ventilatory responses to opioids emerge following repeated fentanyl administration. These responses coincide with changes in oxygen consumption and inspiratory rhythmogenesis from the preBötzinger complex. These observations advance an understanding of the physiological basis for susceptibility and tolerance among individuals likely to succumb to opioid overdose.

反复使用芬太尼后阿片类药物诱导呼吸抑制期间的不同通气反应。
阿片类药物诱导的呼吸抑制(OIRD)是阿片类药物过量的标志,也是芬太尼使用导致死亡的主要危险因素。虽然阿片类药物重复使用(ROU)会增加死亡风险,但人们对其对呼吸的影响及其控制的理解尚未得到充分解决。我们开发了一个反复使用芬太尼超过5天的小鼠模型,以研究ROU如何影响preBötzinger复合体(preBötC)的呼吸和活动,该复合体是驱动吸气性心律发生的脑干网络。最初使用芬太尼在OIRD期间引起严重的代谢危机,涉及通气和氧气消耗之间的不匹配。在ROU的第5天,77%的小鼠在ROU后表现出适应性通气反应,同时在OIRD期间通气和耗氧量之间的关系得到改善。然而,在剩余的少数群体中,在ROU之后,OIRD期间的适应性反应未能出现。这种差异强调了ROU后通气和代谢结果的异质性。此外,在ROU之后,preBötzinger复合体中的节律发生对mu-阿片受体激动作用的敏感性降低,表明对ROU的适应涉及该脑干网络中中枢介导的变化。这些发现揭示了ROU后的一系列生理变化,通常导致OIRD期间通气和氧合的改善。这种变化——或缺乏这种变化——可能导致阿片类药物使用者的过量易感性不可预测。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.20
自引率
4.10%
发文量
146
审稿时长
2 months
期刊介绍: The American Journal of Physiology-Lung Cellular and Molecular Physiology publishes original research covering the broad scope of molecular, cellular, and integrative aspects of normal and abnormal function of cells and components of the respiratory system. Areas of interest include conducting airways, pulmonary circulation, lung endothelial and epithelial cells, the pleura, neuroendocrine and immunologic cells in the lung, neural cells involved in control of breathing, and cells of the diaphragm and thoracic muscles. The processes to be covered in the Journal include gas-exchange, metabolic control at the cellular level, intracellular signaling, gene expression, genomics, macromolecules and their turnover, cell-cell and cell-matrix interactions, cell motility, secretory mechanisms, membrane function, surfactant, matrix components, mucus and lining materials, lung defenses, macrophage function, transport of salt, water and protein, development and differentiation of the respiratory system, and response to the environment.
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