ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2012
The mu-opioid receptor and the NMDA receptor associate in PAG neurons: implications in pain control.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 162 citations in OpenAlex.
- Evaluation of tramadol human pharmacokinetics and safety after co-administration of magnesium ions in randomized, single- and multiple-dose studies.Pharmacological reports : PR · 2021Trial
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism.The American journal of psychiatry · 2018Trial
- Memantine improves buprenorphine/naloxone treatment for opioid dependent young adults.Drug and alcohol dependence · 2015Trial
- The absolute bioavailability of racemic ketamine from a novel sublingual formulation.British journal of clinical pharmacology · 2014Trial
- The effect of clavulanic acid on the development of tolerance and dependence induced by morphine in mice: role of DRD2 and NR1 genes, oxidative stress, and GDNF protein.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- The influence of magnesium ions on the electrophysiological, analgesic, and BDNF-induced neuromodulation of morphine effects in diabetic rats.Frontiers in pharmacology · 2026Article
- Dermorphin [D-Arg2, Lys4] (1-4) Amide Attenuates Burn Pain by Inhibiting TRPV1/NR2B Mediated Neuroinflammatory Signalling.Molecular neurobiology · 2025Article
- Targeting Excitatory Glutamate Receptors for Morphine Tolerance: A Narrative Review.CNS neuroscience & therapeutics · 2025Review
- Can dextromethorphan-bupropion reduce mental pain in depressed individuals? A generating hypothesis overview perspective.Annals of general psychiatry · 2025Review
- Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?The American journal of psychiatry · 2025Review
- N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Beyond the 5-HTThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Review
- The Many Faces of Histidine Triad Nucleotide Binding Protein 1 (HINT1).ACS pharmacology & translational science · 2023Review
- NMDA Receptor and Its Emerging Role in Cancer.International journal of molecular sciences · 2023Review
- Roles of Phosphorylation of N-Methyl-D-Aspartate Receptor in Chronic Pain.Cellular and molecular neurobiology · 2023Review
- Article
- Calcium-Dependent Interplay of Lithium and Tricyclic Antidepressants, Amitriptyline and Desipramine, onInternational journal of molecular sciences · 2022Article
- Adverse Effects of Repeated, Intravenous Morphine on Recovery after Spinal Cord Injury in Young, Male Rats Are Blocked by a Kappa Opioid Receptor Antagonist.Journal of neurotrauma · 2022Article
- Knowing the Enemy Is Halfway towards Victory: A Scoping Review on Opioid-Induced Hyperalgesia.Journal of clinical medicine · 2022Article
- The opioid system in depression.Neuroscience and biobehavioral reviews · 2022Review
17 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The capacity of opioids to alleviate inflammatory pain is negatively regulated by the glutamate-binding N-methyl-D-aspartate receptor (NMDAR). Increased activity of this receptor complicates the clinical use of opioids to treat persistent neuropathic pain. Immunohistochemical and ultrastructural studies have demonstrated the coexistence of both receptors within single neurons of the CNS, including those in the mesencephalic periaqueductal gray (PAG), a region that is implicated in the opioid control of nociception. We now report that mu-opioid receptors (MOR) and NMDAR NR1 subunits associate in the postsynaptic structures of PAG neurons. Morphine disrupts this complex by protein kinase-C (PKC)-mediated phosphorylation of the NR1 C1 segment and potentiates the NMDAR-CaMKII, pathway that is implicated in morphine tolerance. Inhibition of PKC, but not PKA or GRK2, restored the MOR-NR1 association and rescued the analgesic effect of morphine as well. The administration of N-methyl-D-aspartic acid separated the MOR-NR1 complex, increased MOR Ser phosphorylation, reduced the association of the MOR with G-proteins, and diminished the antinociceptive capacity of morphine. Inhibition of PKA, but not PKC, CaMKII, or GRK2, blocked these effects and preserved morphine antinociception. Thus, the opposing activities of the MOR and NMDAR in pain control affect their relation within neurons of structures such as the PAG. This finding could be exploited in developing bifunctional drugs that would act exclusively on those NMDARs associated with MORs.
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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.