{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:17:06Z","timestamp":1791357426406,"version":"4.3.1"},"reference-count":73,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,1,6]],"date-time":"2018-01-06T00:00:00Z","timestamp":1515196800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"University Hospital Basel","award":["no"],"award-info":[{"award-number":["no"]}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2018,2]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Opioids may inhibit the 5\u2010HT transporter (SERT) and the noradrenaline transporter (NET). NET inhibition may contribute to analgesia, and SERT inhibition or interactions with 5\u2010HT receptors may cause serotonergic toxicity. However, the effects of different opioids on the human SERT, NET and 5\u2010HT receptors have not been sufficiently studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We determined the potencies of different opioids to inhibit the SERT and NET<jats:italic>in vitro<\/jats:italic>using human transporter\u2010transfected HEK293 cells. We also tested binding affinities at 5\u2010HT<jats:sub>1A<\/jats:sub>, 5\u2010HT<jats:sub>2A<\/jats:sub>and 5\u2010HT<jats:sub>2C<\/jats:sub>receptors. Additionally, we assessed clinical cases of the serotonin syndrome associated with each opioid reported by PubMed and a World Health Organization database.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Dextromethorphan, l(R)\u2010methadone, racemic methadone, pethidine, tramadol and tapentadol inhibited the SERT at or close to observed drug plasma or estimated brain concentrations in patients. Tapentadol was the most potent NET inhibitor. Pethidine, tramadol, l(R)\u2010methadone, racemic methadone, dextromethorphan and<jats:italic>O<\/jats:italic>\u2010desmethyltramadol also inhibited the NET. 6\u2010Monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, heroin, hydrocodone, hydromorphone, morphine, oxycodone and oxymorphone did not inhibit the SERT or NET. Fentanyl interacted with 5\u2010HT<jats:sub>1A<\/jats:sub>receptors and methadone, pethidine and fentanyl with 5\u2010HT<jats:sub>2A<\/jats:sub>receptors, in the low micromolar range. Opioids most frequently associated with the serotonin syndrome are tramadol, fentanyl, tapentadol, oxycodone, methadone and dextromethorphan.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Some synthetic opioids interact with the SERT and NET at potentially clinically relevant concentrations. SERT inhibition by tramadol, tapentadol, methadone, dextromethorphan and pethidine may contribute to the serotonin syndrome. Direct effects on 5\u2010HT<jats:sub>1A<\/jats:sub>and\/or 5\u2010HT<jats:sub>2A<\/jats:sub>receptors could be involved with methadone and pethidine.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14105","type":"journal-article","created":{"date-parts":[[2017,12,6]],"date-time":"2017-12-06T05:03:04Z","timestamp":1512536584000},"page":"532-543","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":102,"title":["Opioid\u2010induced inhibition of the human 5\u2010HT and noradrenaline transporters<i>in vitro<\/i>: link to clinical reports of serotonin syndrome"],"prefix":"10.1111","volume":"175","author":[{"given":"Anna","family":"Rickli","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Toxicology, Department of Biomedicine, Department of Internal Medicine University Hospital Basel, University of Basel Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia","family":"Liakoni","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital Bern University Hospital, University of Bern Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius C","family":"Hoener","sequence":"additional","affiliation":[{"name":"Neuroscience Research, pRED, Roche Innovation Center Basel F. Hoffmann\u2010La Roche Ltd Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1765-9659","authenticated-orcid":false,"given":"Matthias E","family":"Liechti","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Toxicology, Department of Biomedicine, Department of Internal Medicine University Hospital Basel, University of Basel Basel 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