Naltrexone blocks alcohol-induced effects on kappa-opioid receptors in the plasma membrane.

Autor: Oasa S; Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SE-17176, Sweden., Sezgin E; Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SE-17165, Sweden., Ma Y; Synthetic Biopolymer Chemistry Core, Beckman Research Institute; City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA., Horne DA; Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA., Radmilović MD; Institute of Physics Belgrade, University of Belgrade, Pregrevica 118, Belgrade, 11080, Serbia., Jovanović-Talisman T; Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA., Martin-Fardon R; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA., Vukojević V; Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SE-17176, Sweden. vladana.vukojevic@ki.se., Terenius L; Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SE-17176, Sweden. Lars.Terenius@ki.se.
Jazyk: angličtina
Zdroj: Translational psychiatry [Transl Psychiatry] 2024 Nov 24; Vol. 14 (1), pp. 477. Date of Electronic Publication: 2024 Nov 24.
DOI: 10.1038/s41398-024-03172-8
Abstrakt: Naltrexone (NTX), a homolog of the opiate antidote naloxone, is an orally active long-acting general opioid receptor antagonist used in the treatment of opiate dependence. NTX is also found to relieve craving for alcohol and is one of few FDA-approved medications for treatment of alcohol use disorder (AUD). While it was early on established that NTX acts by blocking the binding of endogenous opioid peptide ligands released by alcohol, experimental evidence emerged that could not be fully accounted for by this explanation alone, suggesting that NTX may have additional modes of action. Mu- and kappa-opioid receptors (MOP and KOP, respectively) are structurally related G-protein-coupled receptors (GPCRs), but they are anatomically differently distributed and functionally distinct, often mediating opposite responses, with MOP typically promoting euphoria and reward, while KOP is associated with dysphoria and aversive states. While the actions of NTX on MOP are extensively characterized, the interactions with KOP are not. Here, we used sensitive fluorescence-based methods with single-molecule sensitivity to study in live cells the influence of alcohol (ethanol, EtOH) on KOP and the interaction between KOP and NTX. Our data show that alcohol, at relevant concentrations (10-40 mM), alters KOP interactions with the lipid environment in the plasma membrane. The counteracting effects of NTX are exerted by both its canonical action on KOP and its hitherto unrevealed effects on the lateral dynamics and organization of lipids in the plasma membrane. The KOP-specific antagonist LY2444296, in clinical trial for major depressive disorder (MDD), blocks KOP but does not show the full action profile of NTX. The therapeutic effect of NTX treatment in AUD may in part be due to direct actions on KOP and in part due to its effect on the surrounding lipid environment.
Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All experiments were done in the laboratory and did not involve humans or animals. The experiments did not involve tissues from humans or other vertebrates. All experiments were done in accordance with scientific standards.
(© 2024. The Author(s).)
Databáze: MEDLINE
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