title: Morphine induces redox-based changes in global DNA methylation and retrotransposon transcription by inhibition of excitatory amino acid transporter type 3-mediated cysteine uptake.
abstract: Canonically, opioids influence cells by binding to a G protein-coupled opioid receptor, initiating intracellular signaling cascades, such as protein kinase, phosphatidylinositol 3-kinase, and extracellular receptor kinase pathways. This results in several downstream effects, including decreased levels of the reduced form of glutathione (GSH) and elevated oxidative stress, as well as epigenetic changes, especially in retrotransposons and heterochromatin, although the mechanism and consequences of these actions are unclear. We characterized the acute and long-term influence of morphine on redox and methylation status (including DNA methylation levels) in cultured neuronal SH-SY5Y cells. Acting via μ-opioid receptors, morphine inhibits excitatory amino acid transporter type 3-mediated cysteine uptake via multiple signaling pathways, involving different G proteins and protein kinases in a temporal manner. Decreased cysteine uptake was associated with decreases in both the redox and methylation status of neuronal cells, as defined by the ratios of GSH to oxidized forms of glutathione and S-adenosylmethionine to S-adenosylhomocysteine levels, respectively. Further, morphine induced global DNA methylation changes, including CpG sites in long interspersed nuclear elements (LINE-1) retrotransposons, resulting in increased LINE-1 mRNA. Together, these findings illuminate the mechanism by which morphine, and potentially other opioids, can influence neuronal-cell redox and methylation status including DNA methylation. Since epigenetic changes are implicated in drug addiction and tolerance phenomenon, this study could potentially extrapolate to elucidate a novel mechanism of action for other drugs of abuse.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts (M.T., J.S., N.H., R.D.); Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter, Florida (R.D.); and Department of Environmental Epidemiology, Harvard School of Public Health, Boston, Massachusetts (H.-M.B.).
authors.forename: Malav
authors.initials: M
authors.lastname: Trivedi
authors.forename: Jayni
authors.initials: J
authors.lastname: Shah
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Hodgson
authors.forename: Hyang-Min
authors.initials: HM
authors.lastname: Byun
authors.forename: Richard
authors.initials: R
authors.lastname: Deth
mesh_terms: D045744:Cell Line, Tumor; D003545:Cysteine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects* / Q000502:physiology; D050580:Excitatory Amino Acid Transporter 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D009020:Morphine / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D018626:Retroelements / Q000187:drug effects* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology
chemical_list: D050580:Excitatory Amino Acid Transporter 3; D018626:Retroelements; C493400:SLC1A1 protein, human; D009020:Morphine; D003545:Cysteine