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Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?
Marjorie R Levinstein1, Reece C Budinich1, Jordi Bonaventura1
1Biobehavioral Imaging and Molecular Neuropsychopharmacology Section, NIDA, Baltimore (Levinstein, Budinich, Michaelides); Department of Pathology and Experimental Therapeutics, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona (Bonaventura); Neuropharmacology and Pain Group, Neuroscience Program, IDIBELL-Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona (Bonaventura); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford (Schatzberg); Experimental Therapeutics and Pathophysiology Branch, NIMH, Bethesda (Zarate); Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore (Michaelides).
Abstract:
Ketamine is a racemic compound and medication comprised of (S)-ketamine and (R)-ketamine enantiomers and its metabolites. It has been used for decades as a dissociative anesthetic, analgesic, and recreational drug. More recently, ketamine, its enantiomers, and its metabolites have been used or are being investigated for the treatment of refractory depression, as well as for comorbid disorders such as anxiety, obsessive-compulsive, and opioid use disorders. Despite its complex pharmacology, ketamine is referred to as an N-methyl-d-aspartate (NMDA) receptor antagonist. In this review, the authors argue that ketamine's pharmacology should be redefined to include opioid receptors and the endogenous opioid system. They also highlight a potential mechanism of action of ketamine for depression that is attributed to bifunctional, synergistic interactions involving NMDA and opioid receptors.
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