{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:54:13Z","timestamp":1790520853700,"version":"4.1.0"},"reference-count":47,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T00:00:00Z","timestamp":1582070400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T00:00:00Z","timestamp":1582070400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T00:00:00Z","timestamp":1582070400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["DP5-OD023116"],"award-info":[{"award-number":["DP5-OD023116"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008069","name":"University of California, San Francisco","doi-asserted-by":"publisher","award":["Program for Breakthrough Biomedical Research"],"award-info":[{"award-number":["Program for Breakthrough Biomedical Research"]}],"id":[{"id":"10.13039\/100008069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose\u2014 opioid-induced respiratory depression. Here, we identify two primary changes to murine breathing after administering opioids. These changes implicate the brainstem\u2019s breathing circuitry which we confirm by locally eliminating the \u00b5-Opioid receptor. We find the critical brain site is the preB\u00f6tzinger Complex, where the breathing rhythm originates, and use genetic tools to reveal that just 70\u2013140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.<\/jats:p>","DOI":"10.7554\/elife.52694","type":"journal-article","created":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T08:00:47Z","timestamp":1582099247000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.52694","source":"Crossref","is-referenced-by-count":154,"title":["Opioids depress breathing through two small brainstem sites"],"prefix":"10.7554","volume":"9","author":[{"given":"Iris","family":"Bachmutsky","sequence":"first","affiliation":[{"name":"Department of Physiology, University of California-San Francisco, San Francisco, United States"},{"name":"Neuroscience Graduate Program, University of California-San Francisco, San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin Paul","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of California-San Francisco, San Francisco, United States"},{"name":"Biomedical Sciences Graduate Program, University of California-San Francisco, San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eszter","family":"Kish","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of California-San Francisco, San Francisco, United States"},{"name":"Neuroscience Graduate Program, University of California-San Francisco, San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1870-2759","authenticated-orcid":true,"given":"Kevin","family":"Yackle","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of California-San Francisco, San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,2,19]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.resp.2004.06.016","article-title":"Pontine influences on breathing: an overview","volume":"143","author":"Alheid","year":"2004","journal-title":"Respiratory Physiology & Neurobiology"},{"key":"bib2","article-title":"Opioids-depress-breathing-through-two-small-brainstem-sites","volume-title":"Github","author":"Bachmutsky","year":"2020","unstructured":"Bachmutsky I. 2020. Opioids-depress-breathing-through-two-small-brainstem-sites. Github. dbfcc90. https:\/\/github.com\/YackleLab\/Opioids-depress-breathing-through-two-small-brainstem-sites."},{"key":"bib3","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1038\/nn1511","article-title":"Multiple origins of Cajal-Retzius cells at the borders of the developing pallium","volume":"8","author":"Bielle","year":"2005","journal-title":"Nature Neuroscience"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1038\/nn.2622","article-title":"Hindbrain interneurons and axon guidance signaling critical for breathing","volume":"13","author":"Bouvier","year":"2010","journal-title":"Nature Neuroscience"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"6500","DOI":"10.1523\/JNEUROSCI.14-11-06500.1994","article-title":"Topographic organization of respiratory responses to glutamate microstimulation of the parabrachial nucleus in the rat","volume":"14","author":"Chamberlin","year":"1994","journal-title":"The Journal of Neuroscience"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.neuron.2016.07.003","article-title":"Defining preB\u00f6tzinger complex rhythm- and Pattern-Generating neural microcircuits in\u00a0Vivo","volume":"91","author":"Cui","year":"2016","journal-title":"Neuron"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1097\/00000542-200105000-00021","article-title":"Anesthetic potency and influence of morphine and sevoflurane on respiration in mu-opioid receptor knockout mice","volume":"94","author":"Dahan","year":"2001","journal-title":"Anesthesiology"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1002\/cne.903470106","article-title":"Brainstem network controlling descending drive to phrenic motoneurons in rat","volume":"347","author":"Dobbins","year":"1994","journal-title":"The Journal of Comparative Neurology"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/BF00583790","article-title":"Respiratory depression caused by either morphine microinjection or repetitive electrical stimulation in the region of the nucleus parabrachialis of cats","volume":"409","author":"Eguchi","year":"1987","journal-title":"Pfl\u00fcgers Archiv"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1007\/s00429-014-0717-9","article-title":"A mu-delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks","volume":"220","author":"Erbs","year":"2015","journal-title":"Brain Structure and Function"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1146\/annurev-physiol-040510-130049","article-title":"Understanding the rhythm of breathing: so near, yet so far","volume":"75","author":"Feldman","year":"2013","journal-title":"Annual Review of Physiology"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1126\/science.286.5444.1566","article-title":"Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preB\u00f6tzinger complex","volume":"286","author":"Gray","year":"1999","journal-title":"Science"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"14883","DOI":"10.1523\/JNEUROSCI.4031-10.2010","article-title":"Developmental origin of PreBotzinger complex respiratory neurons","volume":"30","author":"Gray","year":"2010","journal-title":"Journal of Neuroscience"},{"key":"bib14","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2013.00007","article-title":"Transcription factors define the neuroanatomical organization of the medullary reticular formation","volume":"7","author":"Gray","year":"2013","journal-title":"Frontiers in Neuroanatomy"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"2653","DOI":"10.1111\/bph.14224","article-title":"The novel \u03bc-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception","volume":"175","author":"Hill","year":"2018","journal-title":"British Journal of Pharmacology"},{"key":"bib16","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.14203","article-title":"Interactions between respiratory oscillators in adult rats","volume":"5","author":"Huckstepp","year":"2016","journal-title":"eLife"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"2120","DOI":"10.1152\/jappl.1996.80.6.2120","article-title":"Modulation of respiratory rhythm in vitro: role of gi\/o protein-mediated mechanisms","volume":"80","author":"Johnson","year":"1996","journal-title":"Journal of Applied Physiology"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1111\/j.1476-5381.1986.tb16263.x","article-title":"Characterization of opioid receptors in the cat carotid body involved in chemosensory depression in vivo","volume":"88","author":"Kirby","year":"1986","journal-title":"British Journal of Pharmacology"},{"key":"bib19","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0081-16.2016","article-title":"Voltage-Dependent rhythmogenic property of respiratory Pre-B\u00f6tzinger complex glutamatergic, Dbx1-Derived, and Somatostatin-Expressing neuron populations revealed by graded optogenetic inhibition","volume":"3","author":"Koizumi","year":"2016","journal-title":"Eneuro"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1113\/jphysiol.2013.258830","article-title":"CrossTalk opposing view: the pre-Botzinger complex is not essential for respiratory depression following systemic administration of opioid analgesics","volume":"592","author":"Lalley","year":"2014","journal-title":"The Journal of Physiology"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"4453","DOI":"10.1113\/JP270822","article-title":"?? opioid receptor activation hyperpolarizes respiratory-controlling K\u00f6lliker-Fuse neurons and suppresses post-inspiratory drive","volume":"593","author":"Levitt","year":"2015","journal-title":"The Journal of Physiology"},{"key":"bib22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008766","article-title":"Opiate-induced suppression of rat hypoglossal motoneuron activity and its reversal by ampakine therapy","volume":"5","author":"Lorier","year":"2010","journal-title":"PLOS ONE"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput cre reporting and characterization system for the whole mouse brain","volume":"13","author":"Madisen","year":"2010","journal-title":"Nature Neuroscience"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1002\/cne.903500307","article-title":"Mu, Delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study","volume":"350","author":"Mansour","year":"1994","journal-title":"The Journal of Comparative Neurology"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1126\/science.1084674","article-title":"5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia","volume":"301","author":"Manzke","year":"2003","journal-title":"Science"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1152\/physiolgenomics.2001.4.3.215","article-title":"In vivo measurement of lung volumes in mice","volume":"4","author":"Mitzner","year":"2001","journal-title":"Physiological Genomics"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.1523\/JNEUROSCI.4611-10.2011","article-title":"PreBotzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression","volume":"31","author":"Montandon","year":"2011","journal-title":"Journal of Neuroscience"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1113\/jphysiol.2013.261974","article-title":"CrossTalk proposal: the preBotzinger complex is essential for the respiratory depression following systemic administration of opioid analgesics","volume":"592","author":"Montandon","year":"2014","journal-title":"The Journal of Physiology"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1073\/pnas.76.1.526","article-title":"Enkephalin inhibits release of substance P from sensory neurons in culture and decreases action potential duration","volume":"76","author":"Mudge","year":"1979","journal-title":"PNAS"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1152\/jn.00188.2009","article-title":"Clinically relevant infusion rates of mu-opioid agonist remifentanil cause bradypnea in decerebrate dogs but not via direct effects in the pre-B\u00f6tzinger complex region","volume":"103","author":"Mustapic","year":"2010","journal-title":"Journal of Neurophysiology"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1093\/bja\/aen094","article-title":"Opioids and the control of respiration","volume":"100","author":"Pattinson","year":"2008","journal-title":"British Journal of Anaesthesia"},{"key":"bib32","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.41555","article-title":"Biophysical mechanisms in the mammalian respiratory oscillator re-examined with a new data-driven computational model","volume":"8","author":"Phillips","year":"2019","journal-title":"eLife"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.resp.2018.06.010","article-title":"The parafacial respiratory group and the control of active expiration","volume":"265","author":"Pisanski","year":"2019","journal-title":"Respiratory Physiology & Neurobiology"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"2430","DOI":"10.1152\/jn.00185.2012","article-title":"Pontine \u03bc-opioid receptors mediate bradypnea caused by intravenous remifentanil infusions at clinically relevant concentrations in dogs","volume":"108","author":"Prkic","year":"2012","journal-title":"Journal of Neurophysiology"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"1930","DOI":"10.1016\/j.celrep.2016.04.069","article-title":"Two pairs of ON and OFF retinal ganglion cells are defined by intersectional patterns of transcription factor expression","volume":"15","author":"Rousso","year":"2016","journal-title":"Cell Reports"},{"key":"bib36","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.12111","article-title":"Identification of the pre-B\u00f6tzinger complex inspiratory center in calibrated 'sandwich'\u00a0slices from newborn mice with fluorescent Dbx1 interneurons","volume":"2","author":"Ruangkittisakul","year":"2014","journal-title":"Physiological Reports"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.15585\/mmwr.mm6450a3","article-title":"'Increases in Drug and Opioid Overdose Deaths \u2013 United States, 2000-2014'","volume":"64","author":"Rudd","year":"2016","journal-title":"MMWR. Morbidity and Mortality Weekly Report"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.15585\/mmwr.mm675152e1","article-title":"Drug and Opioid-Involved overdose deaths \u2014 United States, 2013\u20132017","volume":"67","author":"Scholl","year":"2018","journal-title":"MMWR. Morbidity and Mortality Weekly Report"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1038\/nn.3938","article-title":"Optogenetic perturbation of preB\u00f6tzinger complex inhibitory neurons modulates respiratory pattern","volume":"18","author":"Sherman","year":"2015","journal-title":"Nature Neuroscience"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1126\/science.1683005","article-title":"Pre-B\u00f6tzinger complex: a brainstem region that may generate respiratory rhythm in mammals","volume":"254","author":"Smith","year":"1991","journal-title":"Science"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1038\/nn.2104","article-title":"Silencing preB\u00f6tzinger complex somatostatin-expressing neurons induces persistent apnea in awake rat","volume":"11","author":"Tan","year":"2008","journal-title":"Nature Neuroscience"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/j.neuron.2011.07.026","article-title":"A resource of cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex","volume":"71","author":"Taniguchi","year":"2011","journal-title":"Neuron"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1113\/JP278612","article-title":"Differential impact of two critical respiratory centres in opioid-induced respiratory depression in awake mice","volume":"598","author":"Varga","year":"2020","journal-title":"The Journal of Physiology"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.neuron.2011.05.028","article-title":"Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons","volume":"71","author":"Vong","year":"2011","journal-title":"Neuron"},{"key":"bib45","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.03427","article-title":"Laser ablation of Dbx1 neurons in the pre-B\u00f6tzinger complex stops inspiratory rhythm and impairs output in neonatal mice","volume":"3","author":"Wang","year":"2014","journal-title":"eLife"},{"key":"bib46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0074706","article-title":"Mu opioid receptors on primary afferent nav1.8 neurons contribute to opiate-induced analgesia: insight from conditional knockout mice","volume":"8","author":"Weibel","year":"2013","journal-title":"PLOS ONE"},{"key":"bib47","volume-title":"Respiratory Physiology: The Essentials","author":"West","year":"2005"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/52694\/elife-52694-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/52694\/elife-52694-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/52694","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T20:59:35Z","timestamp":1697057975000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/52694"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,19]]},"references-count":47,"alternative-id":["10.7554\/eLife.52694"],"URL":"https:\/\/doi.org\/10.7554\/elife.52694","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/807297","asserted-by":"object"}],"has-review":[{"id-type":"doi","id":"10.3410\/f.737401882.793575482","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.737401882.793582005","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.52694.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.52694.sa1","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.737401882.793579032","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,19]]},"article-number":"e52694"}}