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Mu opioid receptor (MOR) agonists directly hyperpolarize a population of neurons in the dorsolateral pons, particularly the K\u00f6lliker-Fuse (KF) nucleus, that are key mediators of opioid-induced respiratory depression. However, the projection target and synaptic connections of MOR-expressing KF neurons are unknown. Here, we used retrograde labeling and brain slice electrophysiology to determine that MOR-expressing KF neurons project to respiratory nuclei in the ventrolateral medulla, including the preB\u00f6tzinger complex (preB\u00f6tC) and rostral ventral respiratory group (rVRG). These medullary-projecting, MOR-expressing dorsolateral pontine neurons express FoxP2 and are distinct from calcitonin gene-related peptide-expressing lateral parabrachial neurons. Furthermore, dorsolateral pontine neurons release glutamate onto excitatory preB\u00f6tC and rVRG neurons via monosynaptic projections, which is inhibited by presynaptic opioid receptors. Surprisingly, the majority of excitatory preB\u00f6tC and rVRG neurons receiving MOR-sensitive glutamatergic synaptic input from the dorsolateral pons are themselves hyperpolarized by opioids, suggesting a selective opioid-sensitive circuit from the KF to the ventrolateral medulla. Opioids inhibit this excitatory pontomedullary respiratory circuit by three distinct mechanisms\u2014somatodendritic MORs on dorsolateral pontine and ventrolateral medullary neurons and presynaptic MORs on dorsolateral pontine neuron terminals in the ventrolateral medulla\u2014all of which could contribute to opioid-induced respiratory depression.<\/jats:p>","DOI":"10.7554\/elife.81119","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T07:45:10Z","timestamp":1686728710000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.81119","source":"Crossref","is-referenced-by-count":34,"title":["Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms"],"prefix":"10.7554","volume":"12","author":[{"given":"Jordan T","family":"Bateman","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacology and Therapeutics, Breathing Research and Therapeutics Center, University of Florida","place":["Gainesville, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3634-6594","authenticated-orcid":true,"given":"Erica S","family":"Levitt","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacology and Therapeutics, Breathing Research and Therapeutics Center, University of Florida","place":["Gainesville, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1097\/ALN.0b013e318238bba6","article-title":"Molecular mechanisms of opioid receptor-dependent signaling and behavior","volume":"115","author":"Al-Hasani","year":"2011","journal-title":"Anesthesiology"},{"key":"bib2","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":"bib3","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":"bib4","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":"bib5","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.67523","article-title":"Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network","volume":"10","author":"Baertsch","year":"2021","journal-title":"eLife"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/978-1-4419-5692-7_16","article-title":"Indirect opioid actions on inspiratory pre-B\u00f6tzinger complex neurons in newborn rat brainstem slices","volume":"669","author":"Ballanyi","year":"2010","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1111\/bph.15580","article-title":"Understanding and countering opioid-induced respiratory depression","volume":"180","author":"Bateman","year":"2021","journal-title":"British Journal of Pharmacology"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1126\/science.1058803","article-title":"G protein \u03b2\u03b3 subunit-mediated presynaptic inhibition: regulation of exocytotic fusion downstream of Ca2+ entry","volume":"292","author":"Blackmer","year":"2001","journal-title":"Science"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"4674","DOI":"10.1073\/pnas.072075399","article-title":"Desensitization of mu-opioid receptor-evoked potassium currents: initiation at the receptor, expression at the Effector","volume":"99","author":"Blanchet","year":"2002","journal-title":"PNAS"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1038\/nature25511","article-title":"Encoding of danger by parabrachial CGRP neurons","volume":"555","author":"Campos","year":"2018","journal-title":"Nature"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"63","DOI":"10.18773\/austprescr.1996.063","article-title":"Experimental and clinical pharmacology: opioids - 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