Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network
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, w...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-08-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/67523 |
| _version_ | 1818025014462513152 |
|---|---|
| author | Nathan A Baertsch Nicholas E Bush Nicholas J Burgraff Jan-Marino Ramirez |
| author_facet | Nathan A Baertsch Nicholas E Bush Nicholas J Burgraff Jan-Marino Ramirez |
| author_sort | Nathan A Baertsch |
| collection | DOAJ |
| description | 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 preBötzinger Complex (preBötC). To unravel the cellular- and network-level consequences of MOR activation in the preBötC, 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 preBötC 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. |
| first_indexed | 2024-12-10T04:09:22Z |
| format | Article |
| id | doaj.art-4feada1ac7f945d097e3d767bf68db6e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:09:22Z |
| publishDate | 2021-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4feada1ac7f945d097e3d767bf68db6e2022-12-22T02:02:46ZengeLife Sciences Publications LtdeLife2050-084X2021-08-011010.7554/eLife.67523Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating networkNathan A Baertsch0https://orcid.org/0000-0003-1589-5575Nicholas E Bush1Nicholas J Burgraff2Jan-Marino Ramirez3https://orcid.org/0000-0002-5626-3999Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States; Department of Pediatrics, University of Washington, Seattle, United StatesCenter for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United StatesCenter for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United StatesCenter for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States; Department of Pediatrics, University of Washington, Seattle, United States; Department Neurological Surgery, University of Washington, Seattle, United StatesThe 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 preBötzinger Complex (preBötC). To unravel the cellular- and network-level consequences of MOR activation in the preBötC, 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 preBötC 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.https://elifesciences.org/articles/67523breathingopioidrhythm-generationpre-bӧtzinger complexOprm1respiratory depression |
| spellingShingle | Nathan A Baertsch Nicholas E Bush Nicholas J Burgraff Jan-Marino Ramirez Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network eLife breathing opioid rhythm-generation pre-bӧtzinger complex Oprm1 respiratory depression |
| title | Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network |
| title_full | Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network |
| title_fullStr | Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network |
| title_full_unstemmed | Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network |
| title_short | Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network |
| title_sort | dual mechanisms of opioid induced respiratory depression in the inspiratory rhythm generating network |
| topic | breathing opioid rhythm-generation pre-bӧtzinger complex Oprm1 respiratory depression |
| url | https://elifesciences.org/articles/67523 |
| work_keys_str_mv | AT nathanabaertsch dualmechanismsofopioidinducedrespiratorydepressionintheinspiratoryrhythmgeneratingnetwork AT nicholasebush dualmechanismsofopioidinducedrespiratorydepressionintheinspiratoryrhythmgeneratingnetwork AT nicholasjburgraff dualmechanismsofopioidinducedrespiratorydepressionintheinspiratoryrhythmgeneratingnetwork AT janmarinoramirez dualmechanismsofopioidinducedrespiratorydepressionintheinspiratoryrhythmgeneratingnetwork |