ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2023
mGluR5 from Primary Sensory Neurons Promotes Opioid-Induced Hyperalgesia and Tolerance by Interacting with and Potentiating Synaptic NMDA Receptors.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- Effects of exercise intervention on physical mobility in stroke patients: a scoping review and research progress.Frontiers in neurology · 2025Pooled it
- Effect of Subanesthetic Doses of Esketamine on Early Postoperative Pain Sensitivity in Patients Undergoing Salpingectomy: A Randomized Clinical Trial.Drug design, development and therapy · 2026Trial
- Individualizing Perioperative Analgesia: Patient-Specific Determinants of Postoperative Pain and Opioid-Related Outcomes.Medicina (Kaunas, Lithuania) · 2026Review
- Sensory neuron BRAF mediates opioid-induced hyperalgesia and tolerance via presynaptic NMDA receptor hyperactivity.The Journal of clinical investigation · 2026Article
- Mechanisms and Cell Type-Dependence of Non-Hebbian Long-Term Potentiation at Primary Afferent Synapses in the Mouse Spinal Superficial Dorsal Horn.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- EGFR activation sensitizes trigeminal NMDA receptors to promote pain and morphine analgesic tolerance in oral cancer.Science signaling · 2026Article
- Tonic GABA and Glycine Inhibition Control Pain Hypersensitivity via Limiting α2δ-1- and mGluR5-Dependent NMDA Receptor Activity at Primary Afferent→Excitatory Neuron Synapses.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- LRRC8A constitutively inhibits pain hypersensitivity in rodent models by restraining NMDA receptor activity at spinal cord synapses.Science translational medicine · 2025Article
- Promising effects of astaxanthin on pain-related behaviors and morphine tolerance in a mouse model of neuropathic pain: Possible involvement of Nrf2 and the NMDA receptor subunit NR2B.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- GαScience signaling · 2025Article
- [4‑(Arylethyl)‑pyrrolo[2,3-d] pyrimidine improves post-traumatic stress disorder in mice by inhibiting mGluR5-regulated ERK1/2-SGK1 signaling pathway].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2025Article
- α2δ-2 regulates synaptic GluK1 kainate receptors in Purkinje cells and motor coordination.Brain : a journal of neurology · 2025Article
- CPEB3 can regulate seizure susceptibility by inhibiting the transcriptional activity of STAT3 on NMDARs expression.Molecular medicine (Cambridge, Mass.) · 2025Article
- Astaxanthin has a beneficial influence on pain-related symptoms and opioid-induced hyperalgesia in mice with diabetic neuropathy-evidence from behavioral studies.Pharmacological reports : PR · 2024Article
- Tiam1-mediated maladaptive plasticity underlying morphine tolerance and hyperalgesia.Brain : a journal of neurology · 2024Article
- METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2.The Journal of clinical investigation · 2024Article
- The interplay between the microbiota and opioid in the treatment of neuropathic pain.Frontiers in microbiology · 2024Review
- Oxycodone withdrawal is associated with increased cocaine self-administration and aberrant accumbens glutamate plasticity in rats.Neuropharmacology · 2024Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Aberrant activation of presynaptic NMDARs in the spinal dorsal horn is integral to opioid-induced hyperalgesia and analgesic tolerance. However, the signaling mechanisms responsible for opioid-induced NMDAR hyperactivity remain poorly identified. Here, we show that repeated treatment with morphine or fentanyl reduced monomeric mGluR5 protein levels in the dorsal root ganglion (DRG) but increased levels of mGluR5 monomers and homodimers in the spinal cord in mice and rats of both sexes. Coimmunoprecipitation analysis revealed that monomeric and dimeric mGluR5 in the spinal cord, but not monomeric mGluR5 in the DRG, directly interacted with GluN1. By contrast, mGluR5 did not interact with μ-opioid receptors in the DRG or spinal cord. Repeated morphine treatment markedly increased the mGluR5-GluN1 interaction and protein levels of mGluR5 and GluN1 in spinal synaptosomes. The mGluR5 antagonist MPEP reversed morphine treatment-augmented mGluR5-GluN1 interactions, GluN1 synaptic expression, and dorsal root-evoked monosynaptic EPSCs of dorsal horn neurons. Furthermore, CRISPR-Cas9-induced conditional mGluR5 knockdown in DRG neurons normalized mGluR5 levels in spinal synaptosomes and NMDAR-mediated EPSCs of dorsal horn neurons increased by morphine treatment. Correspondingly, intrathecal injection of MPEP or conditional mGluR5 knockdown in DRG neurons not only potentiated the acute analgesic effect of morphine but also attenuated morphine treatment-induced hyperalgesia and tolerance. Together, our findings suggest that opioid treatment promotes mGluR5 trafficking from primary sensory neurons to the spinal dorsal horn. Through dimerization and direct interaction with NMDARs, presynaptic mGluR5 potentiates and/or stabilizes NMDAR synaptic expression and activity at primary afferent central terminals, thereby maintaining opioid-induced hyperalgesia and tolerance.
Indexed as
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What Socratic holds
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 Socratic graph.