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Although naloxone (NLX) has been shown to effectively reverse overdoses by conventional opioids, there may be a need for higher or repeated doses of NLX to revert overdoses from highly potent fentanyls. Here, we used positron emission tomography (PET) to assess NLX\u2019s dose-dependence on both its rate of displacement of [<jats:sup>11<\/jats:sup>C]carfentanil ([<jats:sup>11<\/jats:sup>C]CFN) binding and its duration of mu opioid receptor (MOR) occupancy in the male rat brain. We showed that clinically relevant doses of intravenously (IV) administered NLX (0.035\u00a0mg\/kg, Human Equivalent Dose\u00a0(HED) 0.4\u00a0mg; 0.17\u00a0mg\/kg, HED 2\u00a0mg) rapidly displaced the specific binding of [<jats:sup>11<\/jats:sup>C]CFN in the\u00a0thalamus in a dose-dependent manner. Brain MOR occupancy by IV NLX was greater than 90% at 5\u00a0min after NLX administration for both doses, but at 27.3\u00a0min after 0.035\u00a0mg\/kg dose and at 85\u00a0min after 0.17\u00a0mg\/kg NLX, only 50% occupancy remained. This indicates that the duration of NLX occupancy at MORs is short-lived. Overall, these results show that clinically relevant doses of IV NLX can promptly displace fentanyls at brain MORs, but repeated or higher NLX doses may be required to prevent re-narcotization following overdoses with long-acting fentanyls.<\/jats:p>","DOI":"10.1038\/s41598-022-09601-2","type":"journal-article","created":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T14:02:54Z","timestamp":1650376974000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Naloxone\u2019s dose-dependent displacement of [11C]carfentanil and duration of receptor occupancy in the rat brain"],"prefix":"10.1038","volume":"12","author":[{"given":"Yeona","family":"Kang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly A.","family":"O\u2019Conor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C.","family":"Kelleher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Ramsey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abolghasem","family":"Bakhoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth M.","family":"Eisenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Stodden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torben D.","family":"Pearson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeih-San","family":"Liow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna S.","family":"Fowler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Won","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora D.","family":"Volkow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,19]]},"reference":[{"key":"9601_CR1","unstructured":"CDC Grand Rounds: Prescription Drug Overdoses\u2014a U.S. Epidemic. https:\/\/www.cdc.gov\/mmwr\/preview\/mmwrhtml\/mm6101a3.htm (2012)."},{"key":"9601_CR2","unstructured":"Spencer, M. et al. 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