ArticleMolecular pharmacology2014
Morphine induces redox-based changes in global DNA methylation and retrotransposon transcription by inhibition of excitatory amino acid transporter type 3-mediated cysteine uptake.
Article in Molecular pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers, 1 of them a synthesis that pooled it.
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Who cites it
61 citing papers in PubMed, 1 synthesis or guideline pooled it, 95 citations in OpenAlex.
- Drug-Induced Epigenetic Alterations: A Set of Forensic Toxicological Fingerprints?-A Systematic Review.Genes · 2025Pooled it
- Review
- L-Cysteine Ethyl Ester May Overcome Morphine-Induced Respiratory Depression by Activating Muscarinic Receptors.Pharmaceuticals (Basel, Switzerland) · 2026Article
- The mechanism of the JNK signaling pathway in drug addiction : Author list.Journal of molecular medicine (Berlin, Germany) · 2026Review
- Prenatal morphine exposure induces molecular and structural alterations in the developing hippocampus of neonatal rats.Iranian journal of basic medical sciences · 2026Article
- The cystathionine-γ-lyase inhibitor DL-propargylglycine augments the ability of L-cysteine ethyl ester to overcome the adverse effects of morphine on breathing.American journal of physiology. Lung cellular and molecular physiology · 2025Article
- Structural basis of excitatory amino acid transporter 3 substrate recognition.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- piRNA/PIWI pathways and epigenetic crosstalk in human diseases: Molecular insights into HIV-1 infection and drugs of abuse.Molecular therapy. Nucleic acids · 2025Review
- Research progress of DNA methylation on the regulation of substance use disorders and the mechanisms.Frontiers in cellular neuroscience · 2025Review
- Immune gene regulation is associated with age and environmental adversity in a nonhuman primate.Molecular ecology · 2024Article
- Structural basis of the excitatory amino acid transporter 3 substrate recognition.bioRxiv : the preprint server for biology · 2024Article
- Ferroptosis inhibitor ferrostatin-1 attenuates morphine tolerance development in male rats by inhibiting dorsal root ganglion neuronal ferroptosis.The Korean journal of pain · 2024Article
- Unraveling the Hippocampal Molecular and Cellular Alterations behind Tramadol and Tapentadol Neurobehavioral Toxicity.Pharmaceuticals (Basel, Switzerland) · 2024Article
- L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats.Scientific reports · 2024Article
- L-cysteine ethylester reverses the adverse effects of morphine on breathing and arterial blood-gas chemistry while minimally affecting antinociception in unanesthetized rats.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2024Article
- The cell-permeant antioxidant D-thiol ester D-cysteine ethyl ester overcomes physical dependence to morphine in male Sprague Dawley rats.Frontiers in pharmacology · 2024Article
- Article
- The epigenetic signatures of opioid addiction and physical dependence are prevented by D-cysteine ethyl ester and betaine.Frontiers in pharmacology · 2024Article
- An epigenetic synopsis of parental substance use.Epigenomics · 2023Review
- L-cysteine ethyl ester prevents and reverses acquired physical dependence on morphine in male Sprague Dawley rats.Frontiers in pharmacology · 2023Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
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.
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