{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T02:17:01Z","timestamp":1791339421602,"version":"4.3.1"},"reference-count":68,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DA042499"],"award-info":[{"award-number":["DA042499"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DA045463"],"award-info":[{"award-number":["DA045463"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DA054900"],"award-info":[{"award-number":["DA054900"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DA059067"],"award-info":[{"award-number":["DA059067"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007268","name":"Washington University in St. Louis","doi-asserted-by":"publisher","award":["GF0012452"],"award-info":[{"award-number":["GF0012452"]}],"id":[{"id":"10.13039\/100007268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32DA007261"],"award-info":[{"award-number":["T32DA007261"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Millions of Americans suffering from Opioid Use Disorders face a high risk of fatal overdose due to opioid-induced respiratory depression (OIRD). Fentanyl, a powerful synthetic opioid, is a major contributor to the rising rates of overdose deaths. Reversing fentanyl overdoses has proved challenging due to its high potency and the rapid onset of OIRD. We assessed the contributions of central and peripheral mu opioid receptors (MORs) in mediating fentanyl-induced physiological responses. The peripherally restricted MOR antagonist naloxone methiodide (NLXM) both prevented and reversed OIRD to a degree comparable to that of naloxone (NLX), indicating substantial involvement of peripheral MORs to OIRD. Interestingly, NLXM-mediated OIRD reversal did not produce aversive behaviors observed after NLX. We show that neurons in the nucleus of the solitary tract (nTS), the first central synapse of peripheral afferents, exhibit a biphasic activity profile following fentanyl exposure. NLXM pretreatment attenuates this activity, suggesting that these responses are mediated by peripheral MORs. Together, these findings establish a critical role for peripheral MORs, including ascending inputs to the nTS, as sites of dysfunction during OIRD. Furthermore, selective peripheral MOR antagonism could be a promising therapeutic strategy for managing OIRD by sparing CNS-driven acute opioid-associated withdrawal and aversion observed after NLX.<\/jats:p>","DOI":"10.7554\/elife.104469","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T19:25:12Z","timestamp":1733772312000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.104469","source":"Crossref","is-referenced-by-count":12,"title":["Peripheral opioid receptor antagonism alleviates fentanyl-induced cardiorespiratory depression and is devoid of aversive behavior"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8507-8218","authenticated-orcid":true,"given":"Brian C","family":"Ruyle","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Pain Center, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Washington University in St. Louis","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Sarah","family":"Masud","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Pain Center, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Washington University in St. Louis","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Rohith","family":"Kesaraju","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Pain Center, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Washington University in St. Louis","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Mubariz","family":"Tahirkheli","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Pain Center, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Washington University in St. Louis","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Juhi","family":"Modh","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Pain Center, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Washington University in St. Louis","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Caroline G","family":"Roth","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Pain Center, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Washington University in St. Louis","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Sofia","family":"Angulo-Lopera","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Pain Center, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Washington University in St. Louis","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Tania","family":"Lintz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Pain Center, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Washington University in St. Louis","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Jessica A","family":"Higginbotham","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Pain Center, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Washington University in St. Louis","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Nicolas","family":"Massaly","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Pain Center, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Washington University in St. Louis","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3216-2488","authenticated-orcid":true,"given":"Jose A","family":"Mor\u00f3n","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Pain Center, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Neuroscience, Washington University in St. Louis","place":["St. Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Psychiatry, Washington University in St. Louis","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1002\/(SICI)1096-9861(20000626)422:2<181::AID-CNE3>3.0.CO;2-G","type":"journal-article","article-title":"-opioid receptors are present in vagal afferents and their dendritic targets in the medial nucleus tractus solitarius","volume":"422","author":"Aicher","year":"2000","journal-title":"The Journal of Comparative Neurology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1146\/annurev.ph.56.030194.000521","type":"journal-article","article-title":"Nucleus tractus solitarius--gateway to neural circulatory control","volume":"56","author":"Andresen","year":"1994","journal-title":"Annual Review of Physiology"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"13292","DOI":"10.1523\/JNEUROSCI.3502-07.2007","type":"journal-article","article-title":"Visceral afferents directly activate catecholamine neurons in the solitary tract nucleus","volume":"27","author":"Appleyard","year":"2007","journal-title":"The Journal of Neuroscience"},{"key":"bib4","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52694","type":"journal-article","article-title":"Opioids depress breathing through two small brainstem sites","volume":"9","author":"Bachmutsky","year":"2020","journal-title":"eLife"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.1152\/jn.00038.2008","type":"journal-article","article-title":"Organization and properties of GABAergic neurons in solitary tract nucleus (NTS)","volume":"99","author":"Bailey","year":"2008","journal-title":"Journal of Neurophysiology"},{"key":"bib6","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.81119","type":"journal-article","article-title":"Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms","volume":"12","author":"Bateman","year":"2023","journal-title":"eLife"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1111\/bph.15580","type":"journal-article","article-title":"Understanding and countering opioid-induced respiratory depression","volume":"180","author":"Bateman","year":"2023","journal-title":"British Journal of Pharmacology"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"R1031","DOI":"10.1152\/ajpregu.00260.2013","type":"journal-article","article-title":"Knockdown of tyrosine hydroxylase in the nucleus of the solitary tract reduces elevated blood pressure during chronic intermittent hypoxia","volume":"305","author":"Bathina","year":"2013","journal-title":"American Journal of Physiology. Regulatory, Integrative and Comparative Physiology"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"2815","DOI":"10.1152\/jn.00711.2012","type":"journal-article","article-title":"The \u03bc-opioid receptor agonist DAMGO presynaptically suppresses solitary tract-evoked input to neurons in the rostral solitary nucleus","volume":"109","author":"Boxwell","year":"2013","journal-title":"Journal of Neurophysiology"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/0922-4106(94)90195-3","type":"journal-article","article-title":"Characterization of non-conventional opioid binding sites in rat and human lung","volume":"268","author":"Cabot","year":"1994","journal-title":"European Journal of Pharmacology"},{"key":"bib11","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(81)91308-8","type":"journal-article","article-title":"Behavioural effects after high dose naloxone administration to normal volunteers","volume":"318","author":"Cohen","year":"1981","journal-title":"Lancet"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"2025","DOI":"10.1016\/0024-3205(82)90443-x","type":"journal-article","article-title":"Physiological effects of high dose naloxone administration to normal adults","volume":"30","author":"Cohen","year":"1982","journal-title":"Life Sciences"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.neubiorev.2018.12.005","type":"journal-article","article-title":"Fentanyl: receptor pharmacology, abuse potential, and implications for treatment","volume":"106","author":"Comer","year":"2019","journal-title":"Neuroscience and Biobehavioral Reviews"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.neuroscience.2012.07.010","type":"journal-article","article-title":"Opioids inhibit visceral afferent activation of catecholamine neurons in the solitary tract nucleus","volume":"222","author":"Cui","year":"2012","journal-title":"Neuroscience"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1097\/ALN.0000000000002184","type":"journal-article","article-title":"Averting opioid-induced respiratory depression without affecting analgesia","volume":"128","author":"Dahan","year":"2018","journal-title":"Anesthesiology"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"3108","DOI":"10.1021\/acschemneuro.2c00464","type":"journal-article","article-title":"Opioid antagonists from the orvinol series as potential reversal agents for opioid overdose","volume":"13","author":"Disney","year":"2022","journal-title":"ACS Chem Neurosci"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.drugpo.2017.06.005","type":"journal-article","article-title":"Naloxone for heroin, prescription opioid, and illicitly made fentanyl overdoses: challenges and innovations responding to a dynamic epidemic","volume":"46","author":"Fairbairn","year":"2017","journal-title":"The International Journal on Drug Policy"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1007\/BF02180036","type":"journal-article","article-title":"Fentanyl-induced conditional place preference: lack of associated conditional neurochemical events","volume":"96","author":"Finlay","year":"1988","journal-title":"Psychopharmacology"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1124\/jpet.116.239061","type":"journal-article","article-title":"Pharmacologic profile of naloxegol, a peripherally acting \u00b5-opioid receptor antagonist, for the treatment of opioid-induced constipation","volume":"361","author":"Floettmann","year":"2017","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1152\/jn.00478.2023","type":"journal-article","article-title":"Anatomical distribution of \u00b5-opioid receptors, neurokinin-1 receptors, and vesicular glutamate transporter 2 in the mouse brainstem respiratory network","volume":"132","author":"Furdui","year":"2024","journal-title":"Journal of Neurophysiology"},{"key":"bib21","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2021.109101","type":"journal-article","article-title":"Effects of fentanyl on acute locomotor activity, behavioral sensitization, and contextual reward in female and male rats","volume":"229","author":"Gaulden","year":"2021","journal-title":"Drug and Alcohol Dependence"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"2530","DOI":"10.1152\/jn.00429.2004","type":"journal-article","article-title":"Modulation of synaptic transmission in the rat nucleus of the solitary tract by endomorphin-1","volume":"93","author":"Glatzer","year":"2005","journal-title":"Journal of Neurophysiology"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/s0304-3940(03)00951-0","type":"journal-article","article-title":"Distribution of mu receptors in the ventral respiratory group neurons; immunohistochemical and pharmacological studies in decerebrate cats","volume":"351","author":"Haji","year":"2003","journal-title":"Neuroscience Letters"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"111","DOI":"10.4236\/ojmip.2013.33017","type":"journal-article","article-title":"Low-dose morphine elicits ventilatory excitant and depressant responses in conscious rats: Role of peripheral \u03bc-opioid receptors","volume":"3","author":"Henderson","year":"2013","journal-title":"Open Journal of Molecular and Integrative Physiology"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/0006-8993(82)91291-4","type":"journal-article","article-title":"Morphine enhances and depresses Ca2+-dependent responses in visceral primary afferent neurons","volume":"251","author":"Higashi","year":"1982","journal-title":"Brain Research"},{"key":"bib26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.02.013","type":"journal-article","article-title":"Estradiol protects against pain-facilitated fentanyl use via suppression of opioid-evoked dopamine activity in males","volume":"25","author":"Higginbotham","year":"2025","journal-title":"Neuron"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1111\/bph.14860","type":"journal-article","article-title":"Fentanyl depression of respiration: comparison with heroin and morphine","volume":"177","author":"Hill","year":"2020","journal-title":"British Journal of Pharmacology"},{"key":"bib28","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.88420","type":"journal-article","article-title":"Comparative brain-wide mapping of ketamine- and isoflurane-activated nuclei and functional networks in the mouse brain","volume":"12","author":"Hu","year":"2024","journal-title":"eLife"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1016\/0024-3205(86)90294-8","type":"journal-article","article-title":"Effects of opioid antagonists and their quaternary analogs on temperature changes in morphine-dependent rats","volume":"39","author":"Katovich","year":"1986","journal-title":"Life Sciences"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"R1219","DOI":"10.1152\/ajpregu.00028.2012","type":"journal-article","article-title":"Hypoxia activates nucleus tractus solitarii neurons projecting to the paraventricular nucleus of the hypothalamus","volume":"302","author":"King","year":"2012","journal-title":"American Journal of Physiology. Regulatory, Integrative and Comparative Physiology"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"R721","DOI":"10.1152\/ajpregu.00540.2014","type":"journal-article","article-title":"Catecholaminergic neurons projecting to the paraventricular nucleus of the hypothalamus are essential for cardiorespiratory adjustments to hypoxia","volume":"309","author":"King","year":"2015","journal-title":"American Journal of Physiology. Regulatory, Integrative and Comparative Physiology"},{"key":"bib32","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1241578","type":"journal-article","article-title":"Fentanyl-induced reward seeking is sex and dose dependent and is prevented by D-cysteine ethylester","volume":"14","author":"Knauss","year":"2023","journal-title":"Frontiers in Pharmacology"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"339","DOI":"10.5811\/westjem.2020.10.48768","type":"journal-article","article-title":"Nobody wants to be narcan\u2019d: a pilot qualitative analysis of drug users\u2019 perspectives on naloxone","volume":"22","author":"Lai","year":"2021","journal-title":"The Western Journal of Emergency Medicine"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"4453","DOI":"10.1113\/JP270822","type":"journal-article","article-title":"\u03bc 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":"bib35","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/s0014-2999(02)01715-6","type":"journal-article","article-title":"Naloxone methiodide reverses opioid-induced respiratory depression and analgesia without withdrawal","volume":"445","author":"Lewanowitsch","year":"2002","journal-title":"European Journal of Pharmacology"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1016\/s0006-8993(02)04117-3","type":"journal-article","article-title":"Naloxone and its quaternary derivative, naloxone methiodide, have differing affinities for mu, delta, and kappa opioid receptors in mouse brain homogenates","volume":"964","author":"Lewanowitsch","year":"2003","journal-title":"Brain Research"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/0304-3940(96)12894-9","type":"journal-article","article-title":"Effects of peripheral nerve ligation on expression of \u03bc-opioid receptor in sensory ganglion neurons: an immunohistochemical study in dorsal root and nodose ganglion neurons of the rat","volume":"214","author":"Li","year":"1996","journal-title":"Neuroscience Letters"},{"key":"bib38","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.932189","type":"journal-article","article-title":"Nucleus tractus solitarius neurons activated by hypercapnia and hypoxia lack mu opioid receptor expression","volume":"15","author":"Maletz","year":"2022","journal-title":"Frontiers in Molecular Neuroscience"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1002\/cne.903500307","type":"journal-article","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":"bib40","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1124\/jpet.122.001476","type":"journal-article","article-title":"Heroin- and fentanyl-induced respiratory depression in a rat plethysmography model: potency, tolerance, and sex differences","volume":"385","author":"Marchette","year":"2023","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"202","DOI":"10.15585\/mmwr.mm7006a4","type":"journal-article","article-title":"Trends and geographic patterns in drug and synthetic opioid overdose deaths - united states, 2013-2019","volume":"70","author":"Mattson","year":"2021","journal-title":"MMWR. Morbidity and Mortality Weekly Report"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1007\/s12975-012-0229-y","type":"journal-article","article-title":"Gender-specific differences in the central nervous system\u2019s response to anesthesia","volume":"4","author":"Mawhinney","year":"2013","journal-title":"Translational Stroke Research"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1038\/sj.bjp.0706346","type":"journal-article","article-title":"Endogenous opioid mechanisms partially mediate P2X3\/P2X2\/3-related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain","volume":"146","author":"McGaraughty","year":"2005","journal-title":"British Journal of Pharmacology"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.1523\/JNEUROSCI.4611-10.2011","type":"journal-article","article-title":"PreBotzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression","volume":"31","author":"Montandon","year":"2011","journal-title":"The Journal of Neuroscience"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1111\/add.13027","type":"journal-article","article-title":"Naloxone--does over-antagonism matter? Evidence of iatrogenic harm after emergency treatment of heroin\/opioid overdose","volume":"110","author":"Neale","year":"2015","journal-title":"Addiction"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/0306-4522(96)00027-9","type":"journal-article","article-title":"Localization of mu-opioid receptor-like immunoreactivity in the central components of the vagus nerve: A light and electron microscope study in the rat","volume":"73","author":"Nomura","year":"1996","journal-title":"Neuroscience"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1152\/physiol.00015.2020","type":"journal-article","article-title":"Multi-level regulation of opioid-induced respiratory depression","volume":"35","author":"Palkovic","year":"2020","journal-title":"Physiology"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.neubiorev.2019.06.019","type":"journal-article","article-title":"High potency synthetic opioids: curbing the third wave of the opioid crisis","volume":"106","author":"Parida","year":"2019","journal-title":"Neuroscience & Biobehavioral Reviews"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1093\/bja\/aen094","type":"journal-article","article-title":"Opioids and the control of respiration","volume":"100","author":"Pattinson","year":"2008","journal-title":"British Journal of Anaesthesia"},{"key":"bib50","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-57768-3","type":"journal-article","article-title":"The role of peripheral opioid receptors in triggering heroin-induced brain hypoxia","volume":"10","author":"Perekopskiy","year":"2020","journal-title":"Scientific Reports"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.2147\/DDDT.S221278","type":"journal-article","article-title":"The use of peripheral \u03bc-opioid receptor antagonists (pamora) in the management of opioid-induced constipation: an update on their efficacy and safety","volume":"14","author":"Pergolizzi","year":"2020","journal-title":"Drug Design, Development and Therapy"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1097\/ALN.0b013e318167af9a","type":"journal-article","article-title":"Isoflurane differentially modulates inhibitory and excitatory synaptic transmission to the solitary tract nucleus","volume":"108","author":"Peters","year":"2008","journal-title":"Anesthesiology"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1177\/1073858407311100","type":"journal-article","article-title":"The area postrema: a brain monitor and integrator of systemic autonomic state","volume":"14","author":"Price","year":"2008","journal-title":"The Neuroscientist"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1152\/jn.00017.2021","type":"journal-article","article-title":"Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding","volume":"125","author":"Ramirez","year":"2021","journal-title":"Journal of Neurophysiology"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"7608","DOI":"10.1523\/JNEUROSCI.14-12-07608.1994","type":"journal-article","article-title":"Opioid receptors modulate diverse types of calcium channels in the nucleus tractus solitarius of the rat","volume":"14","author":"Rhim","year":"1994","journal-title":"The Journal of Neuroscience"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"R818","DOI":"10.1152\/ajpregu.00135.2019","type":"journal-article","article-title":"The PVN enhances cardiorespiratory responses to acute hypoxia via input to the nTS","volume":"317","author":"Ruyle","year":"2019","journal-title":"American Journal of Physiology. Regulatory, Integrative and Comparative Physiology"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.neuroscience.2012.11.001","type":"journal-article","article-title":"Differential regulation of CDK5 and c-Fos expression by morphine in the brain of lewis and fischer 344 rat strains","volume":"230","author":"Salas","year":"2013","journal-title":"Neuroscience"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","type":"journal-article","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nature Methods"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1038\/npp.2017.181","type":"journal-article","article-title":"Fentanyl-induced brain hypoxia triggers brain hyperglycemia and biphasic changes in brain temperature","volume":"43","author":"Solis","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1126\/science.aai8636","type":"journal-article","article-title":"A nontoxic pain killer designed by modeling of pathological receptor conformations","volume":"355","author":"Spahn","year":"2017","journal-title":"Science"},{"key":"bib61","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1126\/science.6105709","type":"journal-article","article-title":"Evidence for L-glutamate as the neurotransmitter of baroreceptor afferent nerve fibers","volume":"209","author":"Talman","year":"1980","journal-title":"Science"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1002\/(sici)1096-9861(19971117)388:2<169::aid-cne1>3.0.co;2-#","type":"journal-article","article-title":"Expression of c-fos in the rat brainstem after exposure to hypoxia and to normoxic and hyperoxic hypercapnia","volume":"388","author":"Teppema","year":"1997","journal-title":"The Journal of Comparative Neurology"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1111\/j.1369-1600.2007.00070.x","type":"journal-article","article-title":"Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade","volume":"12","author":"Tzschentke","year":"2007","journal-title":"Addiction Biology"},{"key":"bib64","doi-asserted-by":"publisher","first-page":"290","DOI":"10.15585\/mmwr.mm6911a4","type":"journal-article","article-title":"Drug and opioid-involved overdose deaths - united states, 2017-2018","volume":"69","author":"Wilson","year":"2020","journal-title":"MMWR. Morbidity and Mortality Weekly Report"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"e188","DOI":"10.1016\/j.jemermed.2023.05.006","type":"journal-article","article-title":"Systematic review of naloxone dosing and adverse events in the emergency department","volume":"65","author":"Yugar","year":"2023","journal-title":"The Journal of Emergency Medicine"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.resp.2012.06.032","type":"journal-article","article-title":"Activation of opioid \u03bc-receptors, but not \u03b4- or \u03ba-receptors, switches pulmonary C-fiber-mediated rapid shallow breathing into an apnea in anesthetized rats","volume":"183","author":"Zhang","year":"2012","journal-title":"Respiratory Physiology & Neurobiology"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.resp.2016.10.004","type":"journal-article","article-title":"Mu-opioid receptors in the caudomedial NTS are critical for respiratory responses to stimulation of bronchopulmonary C-fibers and carotid body in conscious rats","volume":"235","author":"Zhuang","year":"2017","journal-title":"Respiratory Physiology & Neurobiology"},{"key":"dataset1","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.15042135","type":"dataset","article-title":"Ruyle_Photometry","volume-title":"Zenodo","author":"Higginbotham","year":"2025","unstructured":"Higginbotham JA. 2025. Ruyle_Photometry. Zenodo."}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/104469\/elife-104469-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/104469\/elife-104469-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/104469","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:48:15Z","timestamp":1787564895000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/104469"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,1]]},"references-count":68,"alternative-id":["10.7554\/eLife.104469"],"URL":"https:\/\/doi.org\/10.7554\/elife.104469","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.09.16.613257","asserted-by":"subject"},{"id-type":"doi","id":"10.1101\/2024.09.16.613257","asserted-by":"object"}],"is-same-as":[{"id-type":"doi","id":"10.7554\/eLife.104469.3","asserted-by":"subject"}],"is-version-of":[{"id-type":"doi","id":"10.7554\/eLife.104469.1","asserted-by":"subject"},{"id-type":"doi","id":"10.7554\/eLife.104469.2","asserted-by":"subject"}],"is-supplemented-by":[{"id-type":"doi","id":"10.5281\/zenodo.15042135","asserted-by":"subject"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,1]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"RP104469"}}