ArticleMolecular pharmacology2020
Regulation of Kappa Opioid Receptor Inactivation Depends on Sex and Cellular Site of Antagonist Action.
Article in Molecular pharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- Repeated fentanyl abstinence intensifies opioid withdrawal and induces a proinflammatory state in striatal microglia.Psychopharmacology · 2026Article
- Nalmefene and naltrexone reduce alcohol intake via selective efficacy in subpopulations distinguished by behavioral and blood-based biomarkers.Communications medicine · 2026Article
- G Protein Inactivation as a Mechanism for Addiction Treatment.Biological psychiatry · 2026Article
- Repeated fentanyl abstinence intensifies opioid withdrawal and induces a proinflammatory state in striatal microglia.bioRxiv : the preprint server for biology · 2025Article
- KOR agonists for the treatment and/or prevention of opioid use disorder and cocaine use disorder.Pharmacology, biochemistry, and behavior · 2025Review
- Decoding the κ Opioid Receptor (KOR): Advancements in Structural Understanding and Implications for Opioid Analgesic Development.Molecules (Basel, Switzerland) · 2024Review
- Systemic kappa opioid receptor antagonism accelerates reinforcement learning via augmentation of novelty processing in male mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
- Effects of prenatal opioid exposure on synaptic adaptations and behaviors across development.Neuropharmacology · 2023Review
- Aticaprant (Clinically Developed Kappa-Opioid Receptor Antagonist) Combined With Naltrexone Prevents Alcohol "Relapse" Drinking.Journal of pharmaceutics & pharmacology · 2022Article
- Article
- Traumatic Stress-Induced Vulnerability to Addiction: Critical Role of the Dynorphin/Kappa Opioid Receptor System.Frontiers in pharmacology · 2022Review
- Release of endogenous dynorphin opioids in the prefrontal cortex disrupts cognition.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2021Article
- Consideration of sex as a biological variable in the translation of pharmacotherapy for stress-associated drug seeking.Neurobiology of stress · 2021Review
- A midbrain dynorphin circuit promotes threat generalization.Current biology : CB · 2021Article
- Replacing a Palatable High-Fat Diet with a Low-Fat Alternative Heightens κ-Opioid Receptor Control over Nucleus Accumbens Dopamine.Nutrients · 2021Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The prototypical member of the receptor-inactivating kappa opioid receptor (KOR) antagonists, norbinaltorphimine (norBNI), produces prolonged receptor inactivation by a cJun kinase mechanism. These antagonists have potential therapeutic utility in the treatment of stress disorders; however, additional preclinical characterization is necessary to understand important aspects of their action. In this study, we report that norBNI does not work as effectively in female mice as in males because of estrogen regulation of G protein receptor kinase (GRK); pretreatment of ovary-intact female mice with the selective GRK2/3 inhibitor, Compound 101, made females equally sensitive to norBNI as males. Prior observations suggested that in vivo treatment with norBNI does not produce long-lasting inhibition of KOR regulation of dopamine release in the nucleus accumbens. We assessed the persistence of norBNI receptor inactivation in subcellular compartments. Fast-scan cyclic voltammetry recordings confirmed that presynaptic inhibition of dopamine release by the KOR agonist U69,593 was not blocked by in vivo pretreatment with norBNI under conditions that prevented KOR-mediated aversion and analgesia. We employed a novel in vivo proxy sensor of KOR activation, adenovirus associated double floxed inverted-HyPerRed, and demonstrated that KOR activation stimulates cJun kinase-dependent reactive oxygen species (ROS) production in somatic regions of ventral tegmental area dopamine neurons, but did not activate ROS production in dopamine terminals. The compartment selective action helps explain how dopamine somatic, but not terminally expressed, KORs are inactivated by norBNI. These results further elucidate molecular signaling mechanisms mediating receptor-inactivating KOR antagonist action and advance medication development for this novel class of stress-resilience medications. SIGNIFICANCE STATEMENT: Kappa opioid receptor (KOR) antagonists are being developed as novel proresilience therapeutics for the treatment of mood and substance use disorders. This study showed that the long-acting KOR antagonists are affected by both the sex of the animal and the subcellular compartment in which the receptor is expressed.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.