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A novel redox‐based epigenetic signaling mechanism for opioids
Author(s) -
TRIVEDI MALAV,
Hodgson Nate,
Shah Jayni,
Deth Richard
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1180.8
Subject(s) - epigenetics , dna methylation , methylation , glutathione , chemistry , pharmacology , microbiology and biotechnology , gene expression , biology , biochemistry , gene , enzyme
Objective To study the involvement of different opioid receptors and downstream signaling pathways for maintaining redox homeostasis via epigenetic regulation of gene expression. Methods and Results We investigated acute and long‐term effects of selected opioid drugs on EAAT3‐mediated transport of cysteine, a precursor for glutathione (GSH) synthesis. Subsequent changes in GSH/GSSG and methylation capacity were measured. Mechanistic investigations suggested temporal involvement of different G‐proteins and downstream signaling protein‐kinases. 5‐Methyl cytosine levels and global DNA methylation levels were also measured. Genome‐wide mRNA expression microarray analysis revealed temporal effects of morphine on transcription. qRT‐PCR analysis showed changes in mRNA levels of enzymes and transporters involved in GSH synthesis, methylation and transulfuration pathways. Redox and methylation responses upon removal of opioids after a prolonged exposure (in‐vitro washout) was also observed. Our findings suggest a novel mechanism for opioid drugs, involving changes in redox status and global DNA methylation mediated by multiple downstream signaling pathways. This mechanism may contribute to opioid drug abuse, tolerance, withdrawal phenomenon and may lead to development of therapeutic interventions. Funding Agency: National Institute of Drug Abuse.