Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction

Yao Chang Chiang, Ruey Yun Wang, Chieh Liang Huang, Shue Hwa Chen, Wen Jing Ho, Hsien Yuan Lane, Ing Kang Ho, Hwei Ting Yang, Wen Lung Ma

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen-response element single nucleotide polymorphism (ERE-SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R- or S-) of 2-ethylidene-1,5-dimethyl-3,3-dipheny-pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug-seeking behaviour, implicating oestradiol-CYP-EDDP/methadone axis decreasing MMT efficacy. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up-regulates methadone-associated metabolizing enzymes. Oestrogen also ablates chronic methadone administration-induced rewarding response. Mechanism dissection revealed the CC genotype of CYP2B6-ERE-SNP exerts higher ERE sequence alignment score, higher estrogenic response as compared to TT genotype. At last, preclinical study via targeting estrogen signal that tamoxifen (TMX; selective estrogen receptor modulator, SERM) 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-on therapy clinical trial introducing SERM in MMT regimen is suggested.

Original languageEnglish
Pages (from-to)3552-3564
Number of pages13
JournalJournal of Cellular and Molecular Medicine
Volume21
Issue number12
DOIs
Publication statusPublished - Dec 1 2017
Externally publishedYes

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Keywords

  • estrogen
  • methadone maintenance treatment
  • opiate addiction
  • tamoxifen

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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