The epigenetic signatures of opioid addiction and physical dependence are prevented by D-cysteine ethyl ester and betaine.

Autor:	McDonough J; Department of Biological Sciences, Kent State University, Kent, OH, United States., Singhal NK; Department of Biological Sciences, Kent State University, Kent, OH, United States., Getsy PM; Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United States., Knies K; Department of Biological Sciences, Kent State University, Kent, OH, United States., Knauss ZT; Department of Biological Sciences, Kent State University, Kent, OH, United States., Mueller D; Department of Biological Sciences, Kent State University, Kent, OH, United States., Bates JN; Department of Anesthesia, University of Iowa Hospitals and Clinics, Iowa City, IA, United States., Damron DS; Department of Biological Sciences, Kent State University, Kent, OH, United States., Lewis SJ; Department of Biological Sciences, Kent State University, Kent, OH, United States.; Department of Pharmacology, Case Western Reserve University, Cleveland, OH, United States.; Functional Electrical Stimulation Center, Case Western Reserve University, Cleveland, OH, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2024 Aug 30; Vol. 15, pp. 1416701. Date of Electronic Publication: 2024 Aug 30 (Print Publication: 2024).
DOI:	10.3389/fphar.2024.1416701
Abstrakt:	We have reported that D,L-thiol esters, including D-cysteine ethyl ester (D-CYSee), are effective at overcoming opioid-induced respiratory depression (OIRD) in rats. Our on-going studies reveal that co-injections of D-CYSee with multi-day morphine injections markedly diminish spontaneous withdrawal that usually occurs after cessation of multiple injections of morphine in rats. Chronically administered opioids are known (1) to alter cellular redox status, thus inducing an oxidative state, and (2) for an overall decrease in DNA methylation, therefore resulting in the transcriptional activation of previously silenced long interspersed elements (LINE-1) retrotransposon genes. The first objective of the present study was to determine whether D-CYSee and the one carbon metabolism with the methyl donor, betaine, would maintain redox control and normal DNA methylation levels in human neuroblastoma cell cultures (SH-SY5Y) under overnight challenge with morphine (100 nM). The second objective was to determine whether D-CYSee and/or betaine could diminish the degree of physical dependence to morphine in male Sprague Dawley rats. Our data showed that overnight treatment with morphine reduced cellular GSH levels, induced mitochondrial damage, decreased global DNA methylation, and increased LINE-1 mRNA expression. These adverse effects by morphine, which diminished the reducing capacity and compromised the maintenance of the membrane potential of SH-SY5Y cells, was prevented by concurrent application of D-CYSee (100 µM) or betaine (300 µM). Furthermore, our data demonstrated that co-injections of D-CYSee (250 μmol/kg, IV) and to a lesser extent, betaine (250 μmol/kg, IV), markedly diminished the development of physical dependence induced by multi-day morphine injections (escalating daily doses of 10-30 mg/kg, IV), as assessed by the lesser number of withdrawal phenomena elicited by the injection of the opioid receptor antagonist, naloxone (1.5 mg/kg, IV). These findings provide evidence that D-CYSee and betaine prevent the appearance of redox alterations and epigenetic signatures commonly seen in neural cells involved in opioid physical dependence/addiction, and lessen development of physical dependence to morphine. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 McDonough, Singhal, Getsy, Knies, Knauss, Mueller, Bates, Damron and Lewis.)
Databáze:	MEDLINE
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