The Effectiveness of Methadone Maintenance Therapy (MMT) on Drug Tolerance, Mediated by Receptor Signaling, Signal Transduction and Intracellular Transport

Abstract Introduction: In chronic drug abuse, opioidergic, dopaminergic signaling, and endocytosis are implicated in neural circuit disruption. We evaluate the impact of Methadone Maintenance Therapy (MMT) on opioid addiction.Method: The expression of dopamine (DRD1- DRD5) and opioid (mu-, delta-, and kappa) receptors, Catechol-O-methyltransferase (COMT), Dynamin 1 like (DNM1L), and RAS-associated (RAB22A) genes in Peripheral Blood Mononuclear Cells from MMT (n= 40) and control (n= 40) were detected by qPCR. Protein-protein interaction (PPI) investigation into addiction-associated genes was performed to elucidate the possible pathways which may have an interference impact on the treatment of addiction.Results: We found that DRD1, DRD2, MOR, DOR, and KOR expressions increased, and the COMT and DNM1L expressions were decreased in MMT. A complex brain network orchestrated by three stages of interactions I) opioid receptors II) Dopamine receptors III) Intracellular vesicular transport (RAB22A), and synaptic vesicle recycling (DNM1L), involved which led to resistance. We elucidate possible pathways that may have an interfering effect on the opioid use disorder (OUD) treatment, and protein-protein interaction (PPI) studies were performed on addiction-associated genes.Conclusion: We introduce Mitogen-Activated Protein Kinase (MAPK) signaling as a significant mediator in addiction and represent DRD2 as a potential therapeutic target for OUD. PPI downstream off-target stimulation may involve ERK activation. Thus, the use of novel agonists and antagonists, in combination with ERK inhibitors, may be of particular interest for future research in addiction treatment.