ArticleProceedings of the National Academy of Sciences of the United States of America2010
Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 103 papers.
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Who cites it
103 citing papers in PubMed, 151 citations in OpenAlex.
- Kappa-Opioid Receptor Antagonism Prolongs the Antidepressant Effects of Ketamine in Adult Mice with Depression-like Behavior Induced by Adolescent Chronic Unpredictable Stress.International journal of molecular sciences · 2026Article
- G Protein Inactivation as a Mechanism for Addiction Treatment.Biological psychiatry · 2026Article
- Narrative review of the scientific and methodological explanations for 101 mechanisms of opioid tolerance.Pain reports · 2025Article
- Prenatal fentanyl exposure affects social dominance and myelination patterns in the adult mouse brain.Neuropharmacology · 2025Article
- Opioid Analgesics: Rise and Fall of Ligand Biased Signaling and Future Perspectives in the Quest for the Holy Grail.CNS drugs · 2025Review
- Buprenorphine Pharmacodynamics: A Bridge to Understanding Buprenorphine Clinical Benefits.Drugs · 2025Review
- Mu opioid receptor activation in microglia enhances HIV-1 infection and HIV-infection-induced inflammatory responses.Frontiers in immunology · 2025Article
- Co-targeting the kappa opioid receptor and dopamine transporter reduces motivation to self-administer cocaine and partially reverses dopamine system dysregulation.Scientific reports · 2024Article
- An Overview of Recent Developments in the Management of Burn Injuries.International journal of molecular sciences · 2023Review
- Mechanisms of cannabinoid tolerance.Biochemical pharmacology · 2023Review
- The YTHDF1-TRAF6 pathway regulates the neuroinflammatory response and contributes to morphine tolerance and hyperalgesia in the periaqueductal gray.Journal of neuroinflammation · 2022Article
- Modulation of 5-HT release by dynorphin mediates social deficits during opioid withdrawal.Neuron · 2022Article
- 14-3-3γ mediates the long-term inhibition of peripheral kappa opioid receptor antinociceptive signaling by norbinaltorphimine.Neuropharmacology · 2022Article
- Opioid receptors signaling network.Journal of cell communication and signaling · 2022Article
- Fentanyl-induced changes in brain activity in awake nonhuman primates at 9.4 Tesla.Brain imaging and behavior · 2022Article
- Agonist-Specific Regulation of G Protein-Coupled Receptors after Chronic Opioid Treatment.Molecular pharmacology · 2022Article
- Nicotine and the developing brain: Insights from preclinical models.Pharmacology, biochemistry, and behavior · 2022Article
- KOR Control over Addiction Processing: An Exploration of the Mesolimbic Dopamine Pathway.Handbook of experimental pharmacology · 2022Article
- Contributions of the International Narcotics Research Conference to Opioid Research Over the Past 50 years.Advances in drug and alcohol research · 2022Review
- Cellular Tolerance Induced by Chronic Opioids in the Central Nervous System.Frontiers in systems neuroscience · 2022Review
43 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Ligand-directed signaling has been suggested as a basis for the differences in responses evoked by otherwise receptor-selective agonists. The underlying mechanisms are not understood, yet clearer definition of this concept may be helpful in the development of novel, pathway-selective therapeutic agents. We previously showed that kappa-opioid receptor activation of JNK by one class of ligand, but not another, caused persistent receptor inactivation. In the current study, we found that the mu-opioid receptor (MOR) could be similarly inactivated by a specific ligand class including the prototypical opioid, morphine. Acute analgesic tolerance to morphine and related opioids (morphine-6-glucuronide and buprenorphine) was blocked by JNK inhibition, but not by G protein receptor kinase 3 knockout. In contrast, a second class of mu-opioids including fentanyl, methadone, and oxycodone produced acute analgesic tolerance that was blocked by G protein receptor kinase 3 knockout, but not by JNK inhibition. Acute MOR desensitization, demonstrated by reduced D-Ala(2)-Met(5)-Glyol-enkephalin-stimulated [(35)S]GTPgammaS binding to spinal cord membranes from morphine-pretreated mice, was also blocked by JNK inhibition; however, desensitization of D-Ala(2)-Met(5)-Glyol-enkephalin-stimulated [(35)S]GTPgammaS binding following fentanyl pretreatment was not blocked by JNK inhibition. JNK-mediated receptor inactivation of the kappa-opioid receptor was evident in both agonist-stimulated [(35)S]GTPgammaS binding and opioid analgesic assays; however, gene knockout of JNK 1 selectively blocked kappa-receptor inactivation, whereas deletion of JNK 2 selectively blocked MOR inactivation. These findings suggest that ligand-directed activation of JNK kinases may generally provides an alternate mode of G protein-coupled receptor regulation.
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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.