{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:27:28Z","timestamp":1790227648576,"version":"4.1.0"},"reference-count":49,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2018,1,1]],"date-time":"2018-01-01T00:00:00Z","timestamp":1514764800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Mol Pain"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>Opioid receptors play an important role in mediating the spinal analgesia. The \u03bc-opioid receptor is the major target of opioid drugs widely used in clinics. However, the regulatory mechanisms of analgesic effect and tolerance for clinical \u03bc-opioid receptor-targeting opioids remain to be fully investigated. Previous studies showed the interaction of \u03b4-opioid receptor with \u03bc-opioid receptor to form the \u03bc-opioid receptor\/\u03b4-opioid receptor heteromers that could be processed in the degradation pathway after \u03b4-opioid receptor agonist treatment. Here, we showed that clinical \u03bc-opioid receptor-targeting opioids, morphine, fentanyl, and methadone, but not tramadol, caused \u03bc-opioid receptor co-internalization with \u03b4-opioid receptors in both transfected human embryonic kidney 293 cells and primary sensory neurons. Prolonged treatment of morphine led to \u03bc-opioid receptor co-degradation with \u03b4-opioid receptors. Furthermore, fentanyl and methadone, but not tramadol, induced the drug tolerance similar to morphine. Thus, the clinical \u03bc-opioid receptor-targeting opioids including morphine, fentanyl, and methadone induce \u03bc-opioid receptor co-internalization with \u03b4-opioid receptors, which may be involved in the analgesic tolerance of these opioids.<\/jats:p>","DOI":"10.1177\/1744806918769492","type":"journal-article","created":{"date-parts":[[2018,3,28]],"date-time":"2018-03-28T01:15:32Z","timestamp":1522199732000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":16,"title":["Clinical opioids differentially induce co-internalization of \u03bc- and \u03b4-opioid receptors"],"prefix":"10.1177","volume":"14","author":[{"given":"Fenghua","family":"Bao","sequence":"first","affiliation":[{"name":"Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China"},{"name":"University of Chinese Academy of 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Jin","family":"Lu","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China"},{"name":"University of Chinese Academy of Sciences, Shanghai, China"},{"name":"Shanghai Clinical Research Center, Chinese Academy of Sciences\/XuHui Central Hospital, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Bao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China"},{"name":"School of Life Science and Technology, ShanghaiTech University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China"},{"name":"University of Chinese Academy of Sciences, Shanghai, China"},{"name":"School of Life Science and Technology, ShanghaiTech University, Shanghai, 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