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There have gender differences reported in response to<jats:styled-content style=\"fixed-case\">MMT<\/jats:styled-content>. This study discovered that the estrogen\u2010response element single nucleotide polymorphism (<jats:styled-content style=\"fixed-case\">ERE<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>; rs16974799, C\/T) of cytochrome 2B6 gene (<jats:italic>cyp2b6<\/jats:italic>; methadone catabolic enzyme) responded differently to<jats:styled-content style=\"fixed-case\">MMT<\/jats:styled-content>dosing. Oestradiol was associated with high<jats:styled-content style=\"fixed-case\">MMT<\/jats:styled-content>dosing, high enantiomer (R\u2010 or S\u2010) of 2\u2010ethylidene\u20101,5\u2010dimethyl\u20103,3\u2010dipheny\u2010pyrrolidine (<jats:styled-content style=\"fixed-case\">EDDP<\/jats:styled-content>; methadone metabolite) to methadone ratio and increased drug\u2010seeking behaviour, implicating oestradiol\u2010<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">EDDP<\/jats:styled-content>\/methadone axis decreasing<jats:styled-content style=\"fixed-case\">MMT<\/jats:styled-content>efficacy. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up\u2010regulates methadone\u2010associated metabolizing enzymes. Oestrogen also ablates chronic methadone administration\u2010induced rewarding response. Mechanism dissection revealed the<jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content>genotype of<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2B6\u2010<jats:styled-content style=\"fixed-case\">ERE<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>exerts higher<jats:styled-content style=\"fixed-case\">ERE<\/jats:styled-content>sequence alignment score, higher estrogenic response as compared to<jats:styled-content style=\"fixed-case\">TT<\/jats:styled-content>genotype. At last, preclinical study<jats:italic>via<\/jats:italic>targeting estrogen signal that tamoxifen (<jats:styled-content style=\"fixed-case\">TMX<\/jats:styled-content>; selective estrogen receptor modulator,<jats:styled-content style=\"fixed-case\">SERM<\/jats:styled-content>) could facilitate the tolerance phase rewarding response of methadone. Strikingly, TMX also reduces tapering\/abstinence phases methadone liability in mice. In conclusion, this study demonstrates altering methadone metabolism through targeting estrogen signals might be able to free morphine addictive patients from the addiction of opioid replacement therapy. Therefore, the add\u2010on therapy clinical trial introducing<jats:styled-content style=\"fixed-case\">SERM<\/jats:styled-content>in<jats:styled-content style=\"fixed-case\">MMT<\/jats:styled-content>regimen is suggested.<\/jats:p>","DOI":"10.1111\/jcmm.13266","type":"journal-article","created":{"date-parts":[[2017,7,12]],"date-time":"2017-07-12T10:17:03Z","timestamp":1499854623000},"page":"3552-3564","source":"Crossref","is-referenced-by-count":23,"title":["Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction"],"prefix":"10.1111","volume":"21","author":[{"given":"Yao\u2010Chang","family":"Chiang","sequence":"first","affiliation":[{"name":"Center for Drug Abuse and Addiction Brain Disease Research Center China Medical University Taichung Taiwan"},{"name":"Department of Nursing Division of Basic Medical Sciences Chang Gong University of Science and Technology Chiayi County 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