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

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.

• Authors: 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
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 21 Issue 12 Pg. 3552-3564 (Dec 2017) ISSN: 1582-4934 [Electronic] England
• PMID: 28699698 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Estrogen Antagonists
• Pyrrolidines
• Tamoxifen
• Estradiol
• CYP2B6 protein, human
• Cytochrome P-450 CYP2B6
• Methadone
• 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine

Topics

• Adult
• Animals
• Cytochrome P-450 CYP2B6 (genetics, metabolism)
• Estradiol (metabolism, pharmacology)
• Estrogen Antagonists (pharmacology)
• Female
• Gene Expression Regulation
• Humans
• Male
• Methadone (pharmacokinetics, pharmacology)
• Mice
• Mice, Inbred C57BL
• Morphine Dependence (drug therapy, genetics, metabolism, physiopathology)
• Opiate Substitution Treatment
• Ovariectomy
• Polymorphism, Single Nucleotide
• Pyrrolidines (metabolism)
• Response Elements
• Sex Factors
• Signal Transduction (drug effects)
• Tamoxifen (pharmacology)