Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network
- Seattle Children's Research Institute, United States
Abstract
The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBӧtzinger Complex (preBӧtC). To unravel the cellular- and network-level consequences of MOR activation in the preBӧtC, MOR- expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBӧtC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: 1) pre-inspiratory spiking is reduced and 2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act synergistically to make the normally robust inspiratory rhythm generating network particularly prone to collapse when challenged with exogenous opioids.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Jan-Marino Ramirez
Funding
National Heart, Lung, and Blood Institute (K99HL145004)
- Nathan A Baertsch
National Heart, Lung, and Blood Institute (R01HL144801)
- Jan-Marino Ramirez
National Heart, Lung, and Blood Institute (F32HL154558)
- Nicholas J Burgraff
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals and approved institutional animal care and use committee (IACUC) protocols at Seattle Children's Research Insitute (Protocol ID: IACUC00058)
Copyright
© 2021, Baertsch et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network
eLife 10:e67523.
https://doi.org/10.7554/eLife.67523
