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To examine the role of peripheral ORs in triggering brain hypoxia, we used oxygen sensors in freely moving rats to examine how naloxone-HCl and naloxone-methiodide, the latter\u00a0which is commonly believed to be peripherally restricted, affect brain oxygen responses induced by intravenous heroin at low, human-relevant doses. Similar to naloxone-HCl, naloxone-methiodide at a relatively low dose (2\u2009mg\/kg) fully blocked heroin-induced decreases in brain oxygen levels. As measured by mass spectrometry, naloxone-methiodide was found to be ~40-fold less permeable than naloxone-HCl across the blood-brain barrier, thus acting as a selective blocker of peripheral ORs. Despite this selectivity, a low but\u00a0detectable amount of naloxone was\u00a0found in brain tissue after naloxone-methiodide administration, potentially influencing our results. Therefore, we examined the effects of naloxone-methiodide at a very low dose (0.2\u2009mg\/kg; at which naloxone was undetectable in brain tissue) and found that this drug still powerfully attenuates heroin-induced brain oxygen responses. These data demonstrate the role of peripheral ORs in triggering heroin-induced respiratory depression and subsequent brain hypoxia.<\/jats:p>","DOI":"10.1038\/s41598-020-57768-3","type":"journal-article","created":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T11:02:51Z","timestamp":1579604571000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The Role of Peripheral Opioid Receptors in Triggering Heroin-induced Brain Hypoxia"],"prefix":"10.1038","volume":"10","author":[{"given":"David","family":"Perekopskiy","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anum","family":"Afzal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shelley N.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludovic","family":"Muller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amina S.","family":"Woods","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugene A.","family":"Kiyatkin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,1,21]]},"reference":[{"key":"57768_CR1","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1093\/bja\/aei145","volume":"94","author":"A Dahan","year":"2005","unstructured":"Dahan, A. et al. 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