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.
Footnotes
- Received January 16, 2014.
- Accepted February 25, 2014.
This work was supported by research grants to R.D. from A2 Corporation Limited and the National Institutes of Health National Institute on Drug Abuse [Grant R21-DA030225]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This work has been previously presented at the following meeting: Trivedi M, Hodgson N, Shah J, and Deth R (2013) A novel redox-based epigenetic signaling mechanism for opioids; Experimental Biology Meeting 2013; 2013 Apr 20–23; Boston, MA.
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- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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