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

研究成果: 雜誌貢獻文章

3 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)3552-3564
頁數13
期刊Journal of Cellular and Molecular Medicine
21
發行號12
DOIs
出版狀態已發佈 - 十二月 1 2017
對外發佈Yes

指紋

Morphine Dependence
Methadone
Estrogens
Therapeutics
Single Nucleotide Polymorphism
Selective Estrogen Receptor Modulators
Morphine
Estradiol
Opiate Substitution Treatment
Genotype
Drug-Seeking Behavior

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

引用此文

Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction. / Chiang, Yao Chang; Wang, Ruey Yun; Huang, Chieh Liang; Chen, Shue Hwa; Ho, Wen Jing; Lane, Hsien Yuan; Ho, Ing Kang; Yang, Hwei Ting; Ma, Wen Lung.

於: Journal of Cellular and Molecular Medicine, 卷 21, 編號 12, 01.12.2017, p. 3552-3564.

研究成果: 雜誌貢獻文章

Chiang, Yao Chang ; Wang, Ruey Yun ; Huang, Chieh Liang ; Chen, Shue Hwa ; Ho, Wen Jing ; Lane, Hsien Yuan ; Ho, Ing Kang ; Yang, Hwei Ting ; Ma, Wen Lung. / Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction. 於: Journal of Cellular and Molecular Medicine. 2017 ; 卷 21, 編號 12. 頁 3552-3564.
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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.",
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AU - Ho, Wen Jing

AU - Lane, Hsien Yuan

AU - Ho, Ing Kang

AU - Yang, Hwei Ting

AU - Ma, Wen Lung

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AB - 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.

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