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Here, we determined the potency, dissociation kinetics and antagonism by naloxone at the \u03bc receptor of several fentanyl and nitazene analogues, compared to morphine and DAMGO.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>In vitro assays of G protein activation and signalling and arrestin recruitment were performed. AtT20 cells expressing \u03bc receptors were loaded with a membrane potential dye and changes in fluorescence used to determine agonist potency, dissociation kinetics and susceptibility to antagonism by naloxone. BRET experiments were undertaken in HEK293T cells expressing \u03bc receptors to assess Gi protein activation and \u03b2\u2010arrestin 2 recruitment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The apparent rate of agonist dissociation from the \u03bc receptor varied: morphine, DAMGO, alfentanil and fentanyl dissociated rapidly, whereas isotonitazene, etonitazene, ohmefentanyl and carfentanil dissociated slowly. Slowly dissociating agonists were more resistant to antagonism by naloxone. For carfentanil, the slow apparent rate of dissociation was not because of G protein receptor kinase\u2010mediated arrestin recruitment as its apparent rate of dissociation was not increased by inhibition of G protein\u2010coupled receptor kinases (GRKs) with Compound 101. The in vitro relative potencies of fentanyls and nitazenes compared to morphine were much lower than that previously observed in in vivo experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>With fentanyls and nitazenes that slowly dissociate from the \u03bc receptor, antagonism by naloxone is pseudo\u2010competitive. In overdoses involving fentanyls and nitazenes, higher doses of naloxone may be required for reversal than those normally used to reverse heroin overdose.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17376","type":"journal-article","created":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T23:00:21Z","timestamp":1729638021000},"page":"969-987","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Slow dissociation kinetics of fentanyls and nitazenes correlates with reduced sensitivity to naloxone reversal at the \u03bc\u2010opioid receptor"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7545-0263","authenticated-orcid":false,"given":"Norah","family":"Alhosan","sequence":"first","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol  Bristol UK"},{"name":"College of Pharmacy Princess Nourah bint Abdulrahman University  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiana","family":"Cavallo","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Santiago","sequence":"additional","affiliation":[{"name":"Macquarie Medical School, Faculty of Medicine Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9183-3993","authenticated-orcid":false,"given":"Eamonn","family":"Kelly","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6050-0048","authenticated-orcid":false,"given":"Graeme","family":"Henderson","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,22]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16177"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16182"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16181"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16178"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.31264"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.forsciint.2020.110553"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.1983.0093"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugpo.2023.104314"},{"key":"e_1_2_13_10_1","unstructured":"Centers for Disease Control and Prevention (CDC). 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