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Opioid-induced respiratory depression (OIRD), mediated by the \u03bc-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preB\u00f6tzinger Complex (preB\u00f6tC). To unravel the cellular- and network-level consequences of MOR activation in the preB\u00f6tC, 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\n                    <jats:italic>-<\/jats:italic>\n                    expressing preB\u00f6tC 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.\n                  <\/jats:p>","DOI":"10.7554\/elife.67523","type":"journal-article","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T08:00:47Z","timestamp":1629187247000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.67523","source":"Crossref","is-referenced-by-count":78,"title":["Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1589-5575","authenticated-orcid":true,"given":"Nathan A","family":"Baertsch","sequence":"first","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute, Seattle, United States"},{"name":"Department of Pediatrics, University of Washington, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas E","family":"Bush","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Burgraff","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5626-3999","authenticated-orcid":true,"given":"Jan-Marino","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute, Seattle, United States"},{"name":"Department of Pediatrics, University of Washington, Seattle, United States"},{"name":"Department Neurological Surgery, University of Washington, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,8,17]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/0306-4522(93)90372-M","article-title":"Characterization of potassium currents in adult rat sensory neurons and modulation by opioids and cyclic AMP","volume":"56","author":"Akins","year":"1993","journal-title":"Neuroscience"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"e168","DOI":"10.1016\/j.bja.2018.12.023","article-title":"Opioid-induced respiratory depression in humans: a review of pharmacokinetic-pharmacodynamic modelling of reversal","volume":"122","author":"Algera","year":"2019","journal-title":"British Journal of Anaesthesia"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/nature18944","article-title":"A novel excitatory network for the control of breathing","volume":"536","author":"Anderson","year":"2016","journal-title":"Nature"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.neuron.2020.02.005","article-title":"Emergent elements of inspiratory rhythmogenesis: network synchronization and synchrony propagation","volume":"106","author":"Ashhad","year":"2020","journal-title":"Neuron"},{"key":"bib5","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.13403","article-title":"Mixed-mode oscillations and population bursting in the pre-B\u00f6tzinger complex","volume":"5","author":"Bacak","year":"2016","journal-title":"eLife"},{"key":"bib6","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52694","article-title":"Opioids depress breathing through two small brainstem sites","volume":"9","author":"Bachmutsky","year":"2020","journal-title":"eLife"},{"key":"bib7","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.62552","article-title":"\u00df-arrestin 2 germline knockout does not attenuate opioid respiratory depression","volume":"10","author":"Bachmutsky","year":"2021","journal-title":"eLife"},{"key":"bib8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03223-x","article-title":"The interdependence of excitation and inhibition for the control of dynamic breathing rhythms","volume":"9","author":"Baertsch","year":"2018","journal-title":"Nature Communications"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"7493","DOI":"10.1073\/pnas.1900523116","article-title":"A spatially dynamic network underlies the generation of inspiratory behaviors","volume":"116","author":"Baertsch","year":"2019","journal-title":"PNAS"},{"key":"bib10","article-title":"oprm1","volume-title":"Software Heritage","author":"Baertsch","year":"2021","unstructured":"Baertsch NA. 2021. oprm1. 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