ArticleCellular signalling2015
Mu opioid receptor stimulation activates c-Jun N-terminal kinase 2 by distinct arrestin-dependent and independent mechanisms.
Article in Cellular signalling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 39 citations in OpenAlex.
- Prenatal fentanyl exposure affects social dominance and myelination patterns in the adult mouse brain.Neuropharmacology · 2025Article
- Identification of c[D-Trp-Phe-β-Ala-β-Ala], the First κ-Opioid Receptor-Specific Negative Allosteric Modulator.ACS pharmacology & translational science · 2024Article
- Astrocytic pyruvate dehydrogenase kinase-lactic acid axis involvement in glia-neuron crosstalk contributes to morphine-induced hyperalgesia in mice.Fundamental research · 2024Article
- JNK Cascade-Induced Apoptosis-A Unique Role in GqPCR Signaling.International journal of molecular sciences · 2023Review
- Multiple p38/JNK mitogen-activated protein kinase (MAPK) signaling pathways mediate salt chemotaxis learning in C. elegans.G3 (Bethesda, Md.) · 2023Article
- Fentanyl-induced changes in brain activity in awake nonhuman primates at 9.4 Tesla.Brain imaging and behavior · 2022Article
- Quantitative Systems Pharmacology and Biased Agonism at Opioid Receptors: A Potential Avenue for Improved Analgesics.International journal of molecular sciences · 2022Review
- Cellular Tolerance Induced by Chronic Opioids in the Central Nervous System.Frontiers in systems neuroscience · 2022Review
- Chronic Treatment with Morphine Disrupts Acute Kinase-Dependent Desensitization of GPCRs.Molecular pharmacology · 2020Article
- A cellular perspective of bias at G protein-coupled receptors.Protein science : a publication of the Protein Society · 2020Review
- c-Jun N terminal kinase signaling pathways mediate cannabinoid tolerance in an agonist-specific manner.Neuropharmacology · 2020Article
- Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist.Frontiers in pharmacology · 2020Article
- Functional characterization of a novel opioid, PZM21, and its effects on the behavioural responses to morphine.British journal of pharmacology · 2019Article
- Reactive oxygen species (ROS) generation is stimulated by κ opioid receptor activation through phosphorylated c-Jun N-terminal kinase and inhibited by p38 mitogen-activated protein kinase (MAPK) activation.The Journal of biological chemistry · 2019Article
- Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment.Neuroscience and biobehavioral reviews · 2019Review
- Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects.Nature communications · 2019Article
- Mitogen-activated protein kinase signaling mediates opioid-induced presynaptic NMDA receptor activation and analgesic tolerance.Journal of neurochemistry · 2019Article
- The Role of G Protein-coupled Receptor Kinases in Cancer.International journal of biological sciences · 2018Review
- Advances in Achieving Opioid Analgesia Without Side Effects.Frontiers in pharmacology · 2018Review
- Src Kinase Inhibition Attenuates Morphine Tolerance without Affecting Reinforcement or Psychomotor Stimulation.Anesthesiology · 2017Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
G protein-coupled receptor desensitization is typically mediated by receptor phosphorylation by G protein-coupled receptor kinase (GRK) and subsequent arrestin binding; morphine, however, was previously found to activate a c-Jun N-terminal kinase (JNK)-dependent, GRK/arrestin-independent pathway to produce mu opioid receptor (MOR) inactivation in spinally-mediated, acute anti-nociceptive responses [Melief et al.] [1]. In the current study, we determined that JNK2 was also required for centrally-mediated analgesic tolerance to morphine using the hotplate assay. We compared JNK activation by morphine and fentanyl in JNK1(-/-), JNK2(-/-), JNK3(-/-), and GRK3(-/-) mice and found that both compounds specifically activate JNK2 in vivo; however, fentanyl activation of JNK2 was GRK3-dependent, whereas morphine activation of JNK2 was GRK3-independent. In MOR-GFP expressing HEK293 cells, treatment with either arrestin siRNA, the Src family kinase inhibitor PP2, or the protein kinase C (PKC) inhibitor Gö6976 indicated that morphine activated JNK2 through an arrestin-independent Src- and PKC-dependent mechanism, whereas fentanyl activated JNK2 through a Src-GRK3/arrestin-2-dependent and PKC-independent mechanism. This study resolves distinct ligand-directed mechanisms of JNK activation by mu opioid agonists and understanding ligand-directed signaling at MOR may improve opioid therapeutics.
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