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Molecular mechanisms of inverse agonism via κ-opioid receptor-G protein complexes.
Nat Chem Biol
January 2025
The Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist.
View Article and Find Full Text PDFThe endogenous dynorphin/kappa opioid receptor (KOR) system in the brain mediates the dysphoric effects of stress, and KOR antagonists may have therapeutic potential for the treatment of drug addiction, depression, and psychosis. One class of KOR antagonists, the long-acting norBNI-like antagonists, have been suggested to act by causing KOR inactivation through a cJun-kinase mechanism rather than by competitive inhibition. In this study, we screened for other opioid ligands that might produce norBNI-like KOR inactivation and found that nalfurafine (a G-biased KOR agonist) and nalmefene (a KOR partial agonist) also produce long-lasting KOR inactivation.
View Article and Find Full Text PDFAcute kappa opioid receptor blocking disrupts the pro-cognitive effect of cannabidiol in neuropathic rats.
Neuropharmacology
December 2024
Department of Experimental Medicine, Division of Pharmacology, Università della Campania "L. Vanvitelli", Naples, Italy.
Cannabidiol has been shown to ameliorate neuropathic pain and its affective components. Previous studies highlighted the pharmacological interaction between the CBD and opioid system, particularly the MOR, but the understanding of the interaction between CBD and kappa opioid receptor (KOR), physiologically stimulated by the endogenous opioid dynorphin, remains elusive. We assessed the pharmacological interactions between CBD and nor-BNI, a selective KOR antagonist in a rat neuropathic pain model.
View Article and Find Full Text PDFEffects of the kappa-opioid receptor antagonist nor-binaltorphimine on methamphetamine-vs-food choice in male rhesus monkeys.
Drug Alcohol Depend
January 2025
Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, NIDA and NIAAA, Bethesda, MD, USA.
Background: Kappa-opioid receptors (KOR) are hypothesized to be involved in mediating ongoing methamphetamine self-administration. Previous rat studies have demonstrated that treatment with the KOR antagonist nor-binaltorphimine (nor-BNI) decreases methamphetamine self-administration. However, KOR antagonist effects on methamphetamine self-administration in nonhuman primates are unknown.
View Article and Find Full Text PDFNaltrexone blocks alcohol-induced effects on kappa-opioid receptors in the plasma membrane.
Transl Psychiatry
November 2024
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SE-17176, Sweden.
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.
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