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Given the limited information about the molecular actions of tapentadol at the \u00b5 receptor, we investigated the intrinsic efficacy of tapentadol and compared it with other opioids. \u03b2\u2010chlornaltrexamine (\u03b2\u2010CNA, 100\u00a0nM, 20\u00a0min) was used to deplete spare receptors in AtT20 cells stably transfected with human \u00b5 receptor wild\u2010type (WT). Opioid\u2010mediated changes in membrane potential were measured in real\u2010time using a membrane potential\u2010sensitive fluorescent dye. Using Black and Leff\u2019s operational model, intrinsic efficacy relative to DAMGO was calculated for each opioid. Tapentadol (0.05\u00a0\u00b1\u00a00.01) activated the GIRK channel with lesser intrinsic efficacy than morphine (0.17\u00a0\u00b1\u00a00.02) and oxycodone (0.16\u00a0\u00b1\u00a00.02). We further assessed the signaling of tapentadol in the common \u00b5 receptor variants (N40D and A6V) which are associated with altered receptor signaling. We found no difference in the response of tapentadol between these receptor variants.<\/jats:p>","DOI":"10.1002\/prp2.921","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T11:45:31Z","timestamp":1643283931000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tapentadol shows lower intrinsic efficacy at \u00b5 receptor than morphine and oxycodone"],"prefix":"10.1002","volume":"10","author":[{"given":"Preeti","family":"Manandhar","sequence":"first","affiliation":[{"name":"Macquarie Medical School Macquarie University  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2538-2001","authenticated-orcid":false,"given":"Mark","family":"Connor","sequence":"additional","affiliation":[{"name":"Macquarie Medical School Macquarie University  Sydney New South Wales 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