{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:35Z","timestamp":1792790435962,"version":"4.5.0"},"reference-count":59,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T00:00:00Z","timestamp":1615766400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T00:00:00Z","timestamp":1615766400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T00:00:00Z","timestamp":1615766400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015150","name":"St. Michael's Hospital Foundation","doi-asserted-by":"crossref","award":["RIC"],"award-info":[{"award-number":["RIC"]}],"id":[{"id":"10.13039\/100015150","id-type":"DOI","asserted-by":"crossref"}]},{"name":"J. P. Bickel Foundation","award":["Medical Grant"],"award-info":[{"award-number":["Medical Grant"]}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    An opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish (\n                    <jats:italic>Danio rerio<\/jats:italic>\n                    ) is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by \u03bc-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.\n                  <\/jats:p>","DOI":"10.7554\/elife.63407","type":"journal-article","created":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T09:01:56Z","timestamp":1615798916000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.63407","source":"Crossref","is-referenced-by-count":31,"title":["Respiratory depression and analgesia by opioid drugs in freely behaving larval zebrafish"],"prefix":"10.7554","volume":"10","author":[{"given":"Shenhab","family":"Zaig","sequence":"first","affiliation":[{"name":"Keenan Research Centre for Biomedical Sciences. St. Michael\u2019s Hospital Unity Health Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5576-3468","authenticated-orcid":true,"given":"Carolina","family":"da Silveira Scarpellini","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3587-4472","authenticated-orcid":true,"given":"Gaspard","family":"Montandon","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Sciences. St. Michael\u2019s Hospital Unity Health Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,3,15]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/nmeth.2434","article-title":"Whole-brain functional imaging at cellular resolution using light-sheet microscopy","volume":"10","author":"Ahrens","year":"2013","journal-title":"Nature Methods"},{"key":"bib2","doi-asserted-by":"publisher","DOI":"10.3791\/4196","article-title":"Regular care and maintenance of a zebrafish (Danio rerio) laboratory: an introduction","volume":"1","author":"Avdesh","year":"2012","journal-title":"Journal of Visualized Experiments"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1146\/annurev-pharmtox-010919-023238","article-title":"TRP channel cooperation for nociception: therapeutic opportunities","volume":"61","author":"Bamps","year":"2021","journal-title":"Annual Review of Pharmacology and Toxicology"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1007\/s10571-011-9755-5","article-title":"Opioid receptor trafficking and signaling: what happens after opioid receptor activation?","volume":"32","author":"Bian","year":"2012","journal-title":"Cellular and Molecular Neurobiology"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.resp.2014.09.003","article-title":"Neural mechanisms underlying respiratory rhythm generation in the lamprey","volume":"224","author":"Bongianni","year":"2016","journal-title":"Respiratory Physiology & Neurobiology"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1097\/00000542-200610000-00009","article-title":"Recurrent hypoxemia in children is associated with increased analgesic sensitivity to opiates","volume":"105","author":"Brown","year":"2006","journal-title":"Anesthesiology"},{"key":"bib7","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.09275","article-title":"Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation","volume":"4","author":"Chen","year":"2015","journal-title":"eLife"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"9104","DOI":"10.1523\/JNEUROSCI.0299-13.2013","article-title":"Neuronal mechanisms of respiratory pattern generation are evolutionary conserved","volume":"33","author":"Cinelli","year":"2013","journal-title":"Journal of Neuroscience"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1097\/ALN.0b013e3181c38c25","article-title":"Incidence, reversal, and prevention of Opioid-induced respiratory depression","volume":"112","author":"Dahan","year":"2010","journal-title":"Anesthesiology"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1097\/ALN.0000000000002184","article-title":"Averting Opioid-induced respiratory depression without affecting analgesia","volume":"128","author":"Dahan","year":"2018","journal-title":"Anesthesiology"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1093\/bja\/ael011","article-title":"Acute effects of fentanyl on breathing pattern in anaesthetized subjects","volume":"96","author":"Ferguson","year":"2006","journal-title":"British Journal of Anaesthesia"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1097\/MLR.0000000000000625","article-title":"The economic burden of prescription opioid overdose, abuse, and dependence in the united states, 2013","volume":"54","author":"Florence","year":"2016","journal-title":"Medical Care"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"8","DOI":"10.12927\/hcq.2016.24568","article-title":"Opioid use and overdose: what we've learned in Ontario","volume":"18","author":"Gomes","year":"2016","journal-title":"Healthcare Quarterly"},{"key":"bib14","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":"bib15","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1021\/jm058286b","volume-title":"Goodman and Gilmans's the Pharmacological Basis for Therapeutics","author":"Gutstein","year":"2001"},{"key":"bib16","volume-title":"IASP Statement on Opioids","author":"IASP","year":"2018","unstructured":"IASP. 2018. IASP Statement on Opioids. https:\/\/www.iasp-pain.org\/Advocacy\/OpioidPositionStatement."},{"key":"bib17","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1046\/j.1460-9568.1999.00420.x","article-title":"Pontine and medullary control of the respiratory activity in the trigeminal and facial nerves of the newborn mouse: an in vitro study","volume":"11","author":"Jacquin","year":"1999","journal-title":"European Journal of Neuroscience"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1177\/2049463720911986","article-title":"Basic opioid pharmacology - An update","volume":"14","author":"James","year":"2020","journal-title":"British Journal of Pain"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.resp.2004.07.019","article-title":"Parabrachial-lateral pontine neurons link nociception and breathing","volume":"143","author":"Jiang","year":"2004","journal-title":"Respiratory Physiology & Neurobiology"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1001\/jama.2013.272","article-title":"Pharmaceutical overdose deaths, united states, 2010","volume":"309","author":"Jones","year":"2013","journal-title":"Jama"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1152\/japplphysiol.90548.2008","article-title":"Micro-opioid receptor agonist injections into the presumed pre-Botzinger complex and the surrounding region of awake goats do not alter eupneic breathing","volume":"107","author":"Krause","year":"2009","journal-title":"Journal of Applied Physiology"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1152\/physrev.00005.2009","article-title":"Reward processing by the opioid system in the brain","volume":"89","author":"Le Merrer","year":"2009","journal-title":"Physiological Reviews"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1242\/jeb.146969","article-title":"Reduction in activity by noxious chemical stimulation is ameliorated by immersion in analgesic drugs in zebrafish","volume":"220","author":"Lopez-Luna","year":"2017","journal-title":"The Journal of Experimental Biology"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.clpt.2005.05.010","article-title":"The 5-hydroxytryptamine 4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression","volume":"78","author":"L\u00f6tsch","year":"2005","journal-title":"Clinical Pharmacology & Therapeutics"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1177\/0310057X1103900405","article-title":"Opioids, ventilation and acute pain management","volume":"39","author":"Macintyre","year":"2011","journal-title":"Anaesthesia and Intensive Care"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1038\/nrd4627","article-title":"Zebrafish as tools for drug discovery","volume":"14","author":"MacRae","year":"2015","journal-title":"Nature Reviews Drug Discovery"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1089\/zeb.2017.1436","article-title":"Adult zebrafish (Danio rerio): An alternative behavioral model of Formalin-Induced nociception","volume":"14","author":"Magalh\u00e3es","year":"2017","journal-title":"Zebrafish"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/nature19112","article-title":"Structure-based discovery of opioid analgesics with reduced side effects","volume":"537","author":"Manglik","year":"2016","journal-title":"Nature"},{"key":"bib29","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":"bib30","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1089\/zeb.2009.0594","article-title":"Mu opioid receptor from the zebrafish exhibits functional characteristics as those of mammalian mu opioid receptor","volume":"6","author":"Marron Fdez de Velasco","year":"2009","journal-title":"Zebrafish"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1097\/ALN.0000000000003403","article-title":"Competitive antagonism of etomidate action by diazepam: in vitro GABAA receptor and in vivo zebrafish studies","volume":"133","author":"McGrath","year":"2020","journal-title":"Anesthesiology"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1124\/jpet.119.264143","article-title":"New author guidelines for displaying data and reporting data analysis and statistical methods in experimental biology","volume":"372","author":"Michel","year":"2020","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.resp.2016.08.007","article-title":"The neural control of respiration in lampreys","volume":"234","author":"Missaghi","year":"2016","journal-title":"Respiratory Physiology & Neurobiology"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1378\/chest.07-1891","article-title":"Central sleep apnea induced by acute ingestion of opioids","volume":"133","author":"Mogri","year":"2008","journal-title":"Chest"},{"key":"bib35","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":"bib36","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1097\/ALN.0000000000001303","article-title":"Distinct cortical signatures associated with sedation and respiratory rate depression by morphine in a pediatric population","volume":"125","author":"Montandon","year":"2016","journal-title":"Anesthesiology"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1097\/ALN.0000000000000984","article-title":"G-protein-gated inwardly rectifying potassium channels modulate respiratory depression by opioids","volume":"124","author":"Montandon","year":"2016","journal-title":"Anesthesiology"},{"key":"bib38","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-50613-2","article-title":"Electrocortical changes associating sedation and respiratory depression by the opioid analgesic fentanyl","volume":"9","author":"Montandon","year":"2019","journal-title":"Scientific Reports"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.chest.2019.05.015","article-title":"Solving the opioid crisis: respiratory depression by opioids as critical end point","volume":"156","author":"Montandon","year":"2019","journal-title":"Chest"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/j.neuroscience.2007.09.028","article-title":"Opioid-induced depression in the lamprey respiratory network","volume":"150","author":"Mutolo","year":"2007","journal-title":"Neuroscience"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1016\/j.neuroscience.2010.06.004","article-title":"Role of neurokinin receptors and ionic mechanisms within the respiratory network of the lamprey","volume":"169","author":"Mutolo","year":"2010","journal-title":"Neuroscience"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/j.bpa.2017.05.004","volume-title":"Best Practive & Research Clinical Anaesthesiology","author":"Nagappa","year":"2017"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1093\/chemse\/bjv091","article-title":"Sensitivities of two zebrafish TRPA1 paralogs to chemical and thermal stimuli analyzed in heterologous expression systems","volume":"41","author":"Oda","year":"2016","journal-title":"Chemical Senses"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1097\/01.fpc.0000220566.90466.a2","article-title":"The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers","volume":"16","author":"Oertel","year":"2006","journal-title":"Pharmacogenetics and Genomics"},{"key":"bib45","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":"bib46","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1164\/rccm.200606-778OC","article-title":"Ampakines alleviate respiratory depression in rats","volume":"174","author":"Ren","year":"2006","journal-title":"American Journal of Respiratory and Critical Care Medicine"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.neuroscience.2007.09.086","article-title":"Developmental expression and distribution of opioid receptors in zebrafish","volume":"151","author":"Sanchez-Simon","year":"2008","journal-title":"Neuroscience"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"R1","DOI":"10.1016\/S0014-2999(97)10016-4","article-title":"The mu-opioid receptor is necessary for [D-Pen2,D-Pen5]enkephalin-induced analgesia","volume":"324","author":"Sora","year":"1997","journal-title":"European Journal of Pharmacology"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.applanim.2013.12.001","article-title":"Antinociceptive effects of buprenorphine in zebrafish larvae: an alternative for rodent models to study pain and nociception?","volume":"152","author":"Steenbergen","year":"2014","journal-title":"Applied Animal Behaviour Science"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.physbeh.2017.03.009","article-title":"A novel zebrafish-based model of nociception","volume":"174","author":"Taylor","year":"2017","journal-title":"Physiology & Behavior"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/S0889-8537(05)70161-9","article-title":"The pharmacology of local anesthetics","volume":"18","author":"Tetzlaff","year":"2000","journal-title":"Anesthesiology Clinics of North America"},{"key":"bib52","doi-asserted-by":"publisher","DOI":"10.12703\/P6-79","article-title":"Opioid-induced respiratory depression: reversal by non-opioid drugs","volume":"6","author":"van der Schier","year":"2014","journal-title":"F1000Prime Reports"},{"key":"bib53","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsz023","article-title":"Newly identified sleep-wake and circadian circuits as potential therapeutic targets","volume":"42","author":"Venner","year":"2019","journal-title":"Sleep"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1016\/j.emc.2015.11.002","article-title":"The opioid epidemic in the united states","volume":"34","author":"Wilkerson","year":"2016","journal-title":"Emergency Medicine Clinics of North America"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1111\/bph.13441","article-title":"Biased ligand quantification in drug discovery: from theory to high throughput screening to identify new biased \u03bc opioid receptor agonists","volume":"173","author":"Winpenny","year":"2016","journal-title":"British Journal of Pharmacology"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1097\/ALN.0000000000002963","article-title":"Drug-selective anesthetic insensitivity of zebrafish lacking \u03b3-Aminobutyric acid type A receptor \u03b23 subunits","volume":"131","author":"Yang","year":"2019","journal-title":"Anesthesiology"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/s11095-007-9440-z","article-title":"Pharmacokinetic-pharmacodynamic modeling of the effectiveness and safety of buprenorphine and fentanyl in rats","volume":"25","author":"Yassen","year":"2008","journal-title":"Pharmaceutical Research"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1213\/ANE.0000000000000607","article-title":"Intrathecal RGS4 inhibitor, CCG50014, reduces nociceptive responses and enhances opioid-mediated analgesic effects in the mouse Formalin test","volume":"120","author":"Yoon","year":"2015","journal-title":"Anesthesia & Analgesia"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1097\/01.anes.0000270760.46821.67","article-title":"Activation of opioid mu receptors in caudal medullary raphe region inhibits the ventilatory response to hypercapnia in anesthetized rats","volume":"107","author":"Zhang","year":"2007","journal-title":"Anesthesiology"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/63407\/elife-63407-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/63407\/elife-63407-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/63407","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:04:51Z","timestamp":1697058291000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/63407"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,15]]},"references-count":59,"alternative-id":["10.7554\/eLife.63407"],"URL":"https:\/\/doi.org\/10.7554\/elife.63407","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.09.30.320267","asserted-by":"object"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.63407.sa1","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.63407.sa2","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,15]]},"article-number":"e63407"}}