{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T22:52:21Z","timestamp":1776898341143,"version":"3.51.2"},"reference-count":97,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sealy Endowment","award":["NS32778"],"award-info":[{"award-number":["NS32778"]}]},{"name":"Sealy Endowment","award":["NS11255"],"award-info":[{"award-number":["NS11255"]}]},{"name":"Sealy Endowment","award":["AR48371 AR48371"],"award-info":[{"award-number":["AR48371 AR48371"]}]},{"name":"Sealy Endowment","award":["BX002695"],"award-info":[{"award-number":["BX002695"]}]},{"name":"NIH","award":["NS32778"],"award-info":[{"award-number":["NS32778"]}]},{"name":"NIH","award":["NS11255"],"award-info":[{"award-number":["NS11255"]}]},{"name":"NIH","award":["AR48371 AR48371"],"award-info":[{"award-number":["AR48371 AR48371"]}]},{"name":"NIH","award":["BX002695"],"award-info":[{"award-number":["BX002695"]}]},{"name":"P01","award":["NS32778"],"award-info":[{"award-number":["NS32778"]}]},{"name":"P01","award":["NS11255"],"award-info":[{"award-number":["NS11255"]}]},{"name":"P01","award":["AR48371 AR48371"],"award-info":[{"award-number":["AR48371 AR48371"]}]},{"name":"P01","award":["BX002695"],"award-info":[{"award-number":["BX002695"]}]},{"name":"R21","award":["NS32778"],"award-info":[{"award-number":["NS32778"]}]},{"name":"R21","award":["NS11255"],"award-info":[{"award-number":["NS11255"]}]},{"name":"R21","award":["AR48371 AR48371"],"award-info":[{"award-number":["AR48371 AR48371"]}]},{"name":"R21","award":["BX002695"],"award-info":[{"award-number":["BX002695"]}]},{"name":"Dana Foundation","award":["NS32778"],"award-info":[{"award-number":["NS32778"]}]},{"name":"Dana Foundation","award":["NS11255"],"award-info":[{"award-number":["NS11255"]}]},{"name":"Dana Foundation","award":["AR48371 AR48371"],"award-info":[{"award-number":["AR48371 AR48371"]}]},{"name":"Dana Foundation","award":["BX002695"],"award-info":[{"award-number":["BX002695"]}]},{"name":"anonymous UTMB endowment","award":["NS32778"],"award-info":[{"award-number":["NS32778"]}]},{"name":"anonymous UTMB endowment","award":["NS11255"],"award-info":[{"award-number":["NS11255"]}]},{"name":"anonymous UTMB endowment","award":["AR48371 AR48371"],"award-info":[{"award-number":["AR48371 AR48371"]}]},{"name":"anonymous UTMB endowment","award":["BX002695"],"award-info":[{"award-number":["BX002695"]}]},{"name":"Merit Review Award","award":["NS32778"],"award-info":[{"award-number":["NS32778"]}]},{"name":"Merit Review Award","award":["NS11255"],"award-info":[{"award-number":["NS11255"]}]},{"name":"Merit Review Award","award":["AR48371 AR48371"],"award-info":[{"award-number":["AR48371 AR48371"]}]},{"name":"Merit Review Award","award":["BX002695"],"award-info":[{"award-number":["BX002695"]}]},{"name":"Office of Research and Development, Medical Research Service, United States Department of Veterans Affairs","award":["NS32778"],"award-info":[{"award-number":["NS32778"]}]},{"name":"Office of Research and Development, Medical Research Service, United States Department of Veterans Affairs","award":["NS11255"],"award-info":[{"award-number":["NS11255"]}]},{"name":"Office of Research and Development, Medical Research Service, United States Department of Veterans Affairs","award":["AR48371 AR48371"],"award-info":[{"award-number":["AR48371 AR48371"]}]},{"name":"Office of Research and Development, Medical Research Service, United States Department of Veterans Affairs","award":["BX002695"],"award-info":[{"award-number":["BX002695"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The N-methyl-D-aspartate (NMDA) glutamate receptors function as plasma membrane ionic channels and take part in very tightly controlled cellular processes activating neurogenic and inflammatory pathways. In particular, the NR1 subunit (new terminology: GluN1) is required for many neuronal and non-neuronal cell functions, including plasticity, survival, and differentiation. Physiologic levels of glutamate agonists and NMDA receptor activation are required for normal neuronal functions such as neuronal development, learning, and memory. When glutamate receptor agonists are present in excess, binding to NMDA receptors produces neuronal\/CNS\/PNS long-term potentiation, conditions of acute pain, ongoing severe intractable pain, and potential excitotoxicity and pathology. The GluNR1 subunit (116 kD) is necessary as the anchor component directing ion channel heterodimer formation, cellular trafficking, and the nuclear localization that directs functionally specific heterodimer formation, cellular trafficking, and nuclear functions. Emerging studies report the relevance of GluN1 subunit composition and specifically that nuclear GluN1 has major physiologic potential in tissue and\/or subnuclear functioning assignments. The shift of the GluN1 subunit from a surface cell membrane to nuclear localization assigns the GluN1 promoter immediate early gene behavior with access to nuclear and potentially nucleolar functions. The present narrative review addresses the nuclear translocation of GluN1, focusing particularly on examples of the role of GluN1 in nociceptive processes.<\/jats:p>","DOI":"10.3390\/ijms241713196","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T08:25:33Z","timestamp":1692951933000},"page":"13196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Pluripotential GluN1 (NMDA NR1): Functional Significance in Cellular Nuclei in Pain\/Nociception"],"prefix":"10.3390","volume":"24","author":[{"given":"Terry A.","family":"McNearney","sequence":"first","affiliation":[{"name":"Department of Neuroscience and Cell Biology, University of Texas Medical Branch Galveston, Galveston, TX 77555-1043, USA"},{"name":"Department of Internal Medicine, University of Texas Medical Branch Galveston, Galveston, TX 77555-1043, USA"},{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch Galveston, Galveston, TX 77555-1043, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7388-4834","authenticated-orcid":false,"given":"Karin N.","family":"Westlund","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA"},{"name":"Biomedical Laboratory Research & Development (121F), New Mexico VA Health Care System, Albuquerque, NM 87108-5153, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"D1282","DOI":"10.1093\/nar\/gkab1010","article-title":"The IUPHAR\/BPS guide to PHARMACOLOGY in 2022: Curating pharmacology for COVID-19, malaria and antibacterials","volume":"50","author":"Harding","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"29394","DOI":"10.1074\/jbc.273.45.29394","article-title":"Activity-dependent Release of Brain-derived Neurotrophic Factor Underlies the Neuroprotective Effect of N-Methyl-d-aspartate","volume":"273","author":"Marini","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1124\/pharmrev.120.000131","article-title":"Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels","volume":"73","author":"Hansen","year":"2021","journal-title":"Pharmacol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"14","DOI":"10.3389\/fnmol.2013.00014","article-title":"Alcohol and NMDA receptor: Current research and future direction","volume":"6","author":"Chandrasekar","year":"2013","journal-title":"Front. Mol. Neurosci."},{"key":"ref_5","unstructured":"Van Dongen, A.M. (2009). Chapter 5 Biology of the NMDA Receptor, Taylor & Francis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00221-009-1760-2","article-title":"The role of TRPV1 receptors in pain evoked by noxious thermal and chemical stimuli","volume":"196","author":"Willis","year":"2009","journal-title":"Exp. Brain Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/0304-3959(92)90266-E","article-title":"The NMDA-receptor antagonist CPP abolishes neurogenic \u2018wind-up pain\u2019 after intrathecal administration in humans","volume":"51","author":"Kristensen","year":"1992","journal-title":"Pain"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Riccardi, A., Guarino, M., Serra, S., Spampinato, M.D., Vanni, S., Shiffer, D., Voza, A., Fabbri, A., De Iaco, F., and on behalf of the Study and Research Center of the Italian Society of Emergency Medicine (2023). Narrative Review: Low-Dose Ketamine for Pain Management. J. Clin. Med., 12.","DOI":"10.3390\/jcm12093256"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5031","DOI":"10.1523\/JNEUROSCI.23-12-05031.2003","article-title":"A Conditional Deletion of the NR1 Subunit of the NMDA Receptor in Adult Spinal Cord Dorsal Horn Reduces NMDA Currents and Injury-Induced Pain","volume":"23","author":"South","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.jad.2023.04.141","article-title":"The effects of ketamine on symptoms of depression and anxiety in real-world care settings: A retrospective controlled analysis","volume":"335","author":"Hietamies","year":"2023","journal-title":"J. Affect. Disord."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.neulet.2015.11.023","article-title":"Overexpression of \u03b1-synuclein simultaneously increases glutamate NMDA receptor phosphorylation and reduces glucocerebrosidase activity","volume":"611","author":"Yang","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Zhang, S., Fu, P., Zhang, Z., Lin, K., Ko, J.K.-S., and Yung, K.K.-L. (2019). Roles of Glutamate Receptors in Parkinson\u2019s Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184391"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"469","DOI":"10.3389\/fnins.2015.00469","article-title":"Chronic Glutamate Toxicity in Neurodegenerative Diseases\u2014What Is the Evidence?","volume":"9","author":"Lewerenz","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.neuron.2006.03.026","article-title":"NMDA Receptors, Glial Cells, and Clinical Medicine","volume":"50","author":"Lipton","year":"2006","journal-title":"Neuron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1007\/s12031-021-01829-3","article-title":"Gut Microbiota Composition and Epigenetic Molecular Changes Connected to the Pathogenesis of Alzheimer\u2019s Disease","volume":"71","author":"Nagu","year":"2021","journal-title":"J. Mol. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23373","DOI":"10.18632\/oncotarget.25169","article-title":"Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors","volume":"9","year":"2018","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"762743","DOI":"10.3389\/fimmu.2021.762743","article-title":"Autoimmune Epilepsy\u2014Novel Multidisciplinary Analysis, Discoveries and Insights","volume":"12","author":"Levite","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1046\/j.1471-4159.2002.00865.x","article-title":"The C-terminal C1 cassette of the N-methyl-d-aspartate receptor 1 subunit contains a bi-partite nuclear localization sequence","volume":"81","author":"Holmes","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.bbrc.2020.11.085","article-title":"The NMDAR GluN1-1a C-terminus binds to CaM and regulates synaptic function","volume":"534","author":"Zhou","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"14163","DOI":"10.1073\/pnas.0802075105","article-title":"Rules of engagement for NMDA receptor subunits","volume":"105","author":"Ulbrich","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15613","DOI":"10.1523\/JNEUROSCI.3314-09.2009","article-title":"Activity-Dependent Anchoring of Importin \u03b1 at the Synapse Involves Regulated Binding to the Cytoplasmic Tail of the NR1-1a Subunit of the NMDA Receptor","volume":"29","author":"Jeffrey","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s10571-021-01185-1","article-title":"Progresses in GluN2A-containing NMDA Receptors and their Selective Regulators","volume":"43","author":"Niu","year":"2023","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"334","DOI":"10.3389\/fncel.2018.00334","article-title":"The C-terminus of NMDAR GluN1-1a Subunit Translocates to Nucleus and Regulates Synaptic Function","volume":"12","author":"Zhou","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_24","first-page":"982","article-title":"Design and Evaluation of Small Interfering RNAs That Target Expression of the N-Methyl-d-aspartate Receptor NR1 Subunit Gene in the Spinal Cord Dorsal Horn","volume":"322","author":"Garraway","year":"2007","journal-title":"Experiment"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Samra, Y.A., Kira, D., Rajpurohit, P., Mohamed, R., Owen, L.A., Shakoor, A., Kim, I.K., DeAngelis, M.M., Sheibani, N., and Al-Shabrawey, M. (2021). Implication of N-Methyl-d-Aspartate Receptor in Homocysteine-Induced Age-Related Macular Degeneration. Int. J. Mol. Sci., 22.","DOI":"10.21203\/rs.3.rs-481688\/v1"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s10571-010-9519-7","article-title":"NMDA Receptors are Expressed in Lymphocytes Activated Both In Vitro and In Vivo","volume":"30","author":"Mashkina","year":"2010","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R584","DOI":"10.1152\/ajpregu.00452.2009","article-title":"A peripheral neuroimmune link: Glutamate agonists upregulate NMDA NR1 receptor mRNA and protein, vimentin, TNF-\u03b1, and RANTES in cultured human synoviocytes","volume":"298","author":"McNearney","year":"2010","journal-title":"Am. J. Physiol. Integr. Comp. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.1002\/art.22829","article-title":"Modulation of interleukin-6 and matrix metalloproteinase 2 expression in human fibroblast-like synoviocytes by functional ionotropic glutamate receptors","volume":"56","author":"Flood","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_29","first-page":"4193","article-title":"Interaction between protein kinase C and actin in megakaryocyte polyploidization","volume":"19","author":"Baatout","year":"1999","journal-title":"Anticancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1182\/blood-2002-11-3553","article-title":"NMDA receptor\u2013mediated regulation of human megakaryocytopoiesis","volume":"102","author":"Hitchcock","year":"2003","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S8756-3282(97)00295-0","article-title":"Glutamate Receptors Are Expressed by Bone Cells and Are Involved in Bone Resorption","volume":"22","author":"Chenu","year":"1998","journal-title":"Bone"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1021\/acschemneuro.1c00841","article-title":"Epigenetic Mechanisms of Neural Plasticity in Chronic Neuropathic Pain","volume":"13","author":"Ghosh","year":"2022","journal-title":"ACS Chem. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"14960","DOI":"10.1073\/pnas.1516016112","article-title":"Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity","volume":"112","author":"Nasca","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"35018","DOI":"10.1074\/jbc.M504108200","article-title":"Transcription of the NR1 Subunit of the N-Methyl-d-aspartate Receptor Is Down-regulated by Excitotoxic Stimulation and Cerebral Ischemia","volume":"280","author":"Deogracias","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1111\/j.1471-4159.2011.07460.x","article-title":"\u03b1-Synuclein promotes clathrin-mediated NMDA receptor endocytosis and attenuates NMDA-induced dopaminergic cell death","volume":"119","author":"Cheng","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1007\/s12551-020-00761-x","article-title":"The rich inner life of the cell nucleus: Dynamic organization, active flows, and emergent rheology","volume":"12","author":"Zidovska","year":"2020","journal-title":"Biophys. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Hua, L., Yan, D., Wan, C., and Hu, B. (2022). Nucleolus and Nucleolar Stress: From Cell Fate Decision to Disease Development. Cells, 11.","DOI":"10.3390\/cells11193017"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1074\/jbc.M107809200","article-title":"The N-Methyl-d-aspartate Receptor Splice Variant NR1\u20134 C-terminal Domain. Deletion analysis and role in subcellular distribution","volume":"277","author":"Holmes","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_39","first-page":"997","article-title":"Synapse to Nucleus Signaling during Long-Term Synaptic Plasticity: A Role for the Classical Active Nuclear Import Pathway","volume":"44","author":"Thompson","year":"2004","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"440","DOI":"10.3389\/fphys.2020.00440","article-title":"Tyrosine Kinase Inhibitors Reduce NMDA NR1 Subunit Expression, Nuclear Translocation, and Behavioral Pain Measures in Experimental Arthritis","volume":"11","author":"Westlund","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0304-3959(99)00311-5","article-title":"Amino acid release into the knee joint: Key role in nociception and inflammation","volume":"86","author":"Lawand","year":"2000","journal-title":"Pain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0165-0173(92)90005-7","article-title":"Neural changes in acute arthritis in monkeys. IV. Time-course of amino acid release into the lumbar dorsal horn","volume":"17","author":"Sorkin","year":"1992","journal-title":"Brain Res. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.1523\/JNEUROSCI.16-13-04283.1996","article-title":"Excitatory Actions of GABA after Neuronal Trauma","volume":"16","author":"Pol","year":"1996","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1038\/nature01868","article-title":"Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain","volume":"424","author":"Coull","year":"2003","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1097\/00001756-199611040-00035","article-title":"Ultrastructural localization of glutamate receptor subunits (NMDAR1, AMPA GluR1 and GluR2\/3) and spinothalamic tract cells","volume":"7","author":"Ye","year":"1996","journal-title":"Neuroreport"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0304-3940(00)01229-5","article-title":"Neuroprotection by MAPK\/ERK kinase inhibition with U0126 against oxidative stress in a mouse neuronal cell line and rat primary cultured cortical neurons","volume":"288","author":"Satoh","year":"2000","journal-title":"Neurosci. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1080\/01616412.2018.1441693","article-title":"U0126 protects hippocampal CA1 neurons against forebrain ischemia-induced apoptosis via the ERK1\/2 signaling pathway and NMDA receptors","volume":"40","author":"Li","year":"2018","journal-title":"Neurol. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0006-8993(94)91956-9","article-title":"Differential effects of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on spinal release of amino acids after development of acute arthritis in rats","volume":"664","author":"Sluka","year":"1994","journal-title":"Brain Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1152\/jn.1993.70.4.1365","article-title":"N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists block the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat\u2019s knee joint","volume":"70","author":"Lucke","year":"1993","journal-title":"J. Neurophysiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1471-4159.1988.tb04845.x","article-title":"Extracellular Amino Acid Concentrations in the Dorsal Spinal Cord of Freely Moving Rats Following Veratridine and Nociceptive Stimulation","volume":"51","author":"Skilling","year":"1988","journal-title":"J. Neurochem."},{"key":"ref_51","first-page":"739","article-title":"Excitatory amino acid profiles of synovial fluid from patients with arthritis","volume":"27","author":"McNearney","year":"2000","journal-title":"J. Rheumatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4107","DOI":"10.1007\/s10072-022-06068-x","article-title":"Anxiety and depression in Alzheimer\u2019s disease: A systematic review of pathogenetic mechanisms and relation to cognitive decline","volume":"43","author":"Botto","year":"2022","journal-title":"Neurol. Sci."},{"key":"ref_53","first-page":"1","article-title":"Transcriptional Factor NF-\u03baB as a Target for Therapy in Parkinson\u2019s Disease","volume":"2011","author":"Flood","year":"2011","journal-title":"Park. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"999509","DOI":"10.3389\/fncel.2022.999509","article-title":"NMDARs mediate peripheral and central sensitization contributing to chronic orofacial pain","volume":"16","author":"Liu","year":"2022","journal-title":"Front. Cell. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1046\/j.1471-4159.2001.00386.x","article-title":"Nuclear factor \u03baB is a critical determinant in N-methyl-d-aspartate receptor-mediated neuroprotection","volume":"78","author":"Lipsky","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.pbb.2004.07.003","article-title":"NMDA-R1 antisense oligodeoxynucleotides modify formalin-induced nociception and spinal c-Fos expression in rat spinal cord","volume":"79","author":"Lee","year":"2004","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1096\/fasebj.13.15.2179","article-title":"The glutamate receptor antagonist MK801 modulates bone resorption in vitro by a mechanism predominantly involving osteoclast differentiation","volume":"13","author":"Peet","year":"1999","journal-title":"FASEB J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.pain.2010.11.026","article-title":"RNA interference-mediated gene silence of the NR1 subunit of the NMDA receptor by subcutaneous injection of vector-encoding short hairpin RNA reduces formalin-induced nociception in the rat","volume":"152","author":"Tan","year":"2011","journal-title":"Pain"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0304-3940(93)90357-Q","article-title":"An experimental arthritis model in rats: The effects of NMDA and non-NMDA antagonists on aspartate and glutamate release in the dorsal horn","volume":"149","author":"Sluka","year":"1993","journal-title":"Neurosci. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1038\/nature04301","article-title":"NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury","volume":"438","author":"Salter","year":"2005","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/aps.2010.190","article-title":"Enhanced NMDA receptor NR1 phosphorylation and neuronal activity in the arcuate nucleus of hypothalamus following peripheral inflammation","volume":"32","author":"Peng","year":"2011","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.brainres.2009.04.038","article-title":"Spinal NMDA NR1 subunit expression following transient TNBS colitis","volume":"1279","author":"Zhou","year":"2009","journal-title":"Brain Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s12974-015-0371-z","article-title":"Endogenous BDNF augments NMDA receptor phosphorylation in the spinal cord via PLC\u03b3, PKC, and PI3K\/Akt pathways during colitis","volume":"12","author":"Liu","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4213928","DOI":"10.1155\/2019\/4213928","article-title":"Effect of Electroacupuncture at Different Acupoints on the Expression of NMDA Receptors in ACC and Colon in IBS Rats","volume":"2019","author":"Tan","year":"2019","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Kim, M., Kim, H., and Kim, H. (2022). Anti-Inflammatory Effect of Protopine through MAPK and NF-\u03baB Signaling Regulation in HepG2 Cell. Molecules, 27.","DOI":"10.3390\/molecules27144601"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1093\/molbev\/msn002","article-title":"Nucleolar Binding Sequences of the Ribosomal Protein S6e Family Reside in Evolutionary Highly Conserved Peptide Clusters","volume":"25","author":"Bisotti","year":"2008","journal-title":"Mol. Biol. Evol."},{"key":"ref_67","first-page":"763","article-title":"Nucleolar binding of an anti-NMDA receptor antibody in hydra: A non-canonical role for an NMDA receptor protein?","volume":"311","author":"Zompa","year":"2009","journal-title":"J. Exp. Zool. Part A Ecol. Integr. Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.acthis.2012.03.005","article-title":"Expression of NMDA receptor subunit 1 in the rat retina","volume":"115","author":"Fan","year":"2013","journal-title":"Acta Histochem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.jphs.2016.12.002","article-title":"Apelin protects against NMDA-induced retinal neuronal death via an APJ receptor by activating Akt and ERK1\/2, and suppressing TNF-\u03b1 expression in mice","volume":"133","author":"Ishimaru","year":"2017","journal-title":"J. Pharmacol. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1023\/A:1007249829659","article-title":"Ionotropic glutamate receptor subunits are differentially regulated in the motoneuronal pools of the rat hypoglossal nucleus in response to axotomy","volume":"29","author":"Gerrikagoitia","year":"2000","journal-title":"J. Neurocytol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1046\/j.1471-4159.2003.02048.x","article-title":"Translationally distinct populations of NMDA receptor subunit NR1 mRNA in the developing rat brain","volume":"87","author":"Awobuluyi","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Irfan, J., Febrianto, M.R., Sharma, A., Rose, T., Mahmudzade, Y., Di Giovanni, S., Nagy, I., and Torres-Perez, J.V. (2022). DNA Methylation and Non-Coding RNAs during Tissue-Injury Associated Pain. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020752"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.2217\/epi-2020-0151","article-title":"Epigenetic-mediated N-methyl-D-aspartate receptor changes in the brain of isolated reared rats","volume":"12","author":"Loureiro","year":"2020","journal-title":"Epigenomics"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5986","DOI":"10.1007\/s12035-021-02518-3","article-title":"Fyn Kinase Activity and Its Role in Neurodegenerative Disease Pathology: A Potential Universal Target?","volume":"58","author":"Guglietti","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"96536","DOI":"10.18632\/oncotarget.22106","article-title":"Human cytomegalovirus and Herpes Simplex type I virus can engage RNA polymerase I for transcription of immediate early genes","volume":"8","author":"Kostopoulou","year":"2017","journal-title":"Oncotarget"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.semcdb.2022.04.001","article-title":"Nucleolar stress: From development to cancer","volume":"136","year":"2023","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_77","first-page":"1","article-title":"HIF-1\u03b1 Ameliorates Diabetic Neuropathic Pain via Parkin-Mediated Mitophagy in a Mouse Model","volume":"2022","author":"He","year":"2022","journal-title":"BioMed Res. Int."},{"key":"ref_78","first-page":"e14182","article-title":"Resveratrol may ameliorate rheumatoid arthritis via the STAT3\/HIF-1\/VEGF molecular pathway","volume":"46","year":"2022","journal-title":"J. Food Biochem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.pain.2008.10.021","article-title":"Regulation of the trigeminal NR1 subunit expression induced by inflammation of the temporomandibular joint region in rats","volume":"141","author":"Wang","year":"2009","journal-title":"Pain"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1080\/01616412.2017.1364515","article-title":"The role and mechanism of glutamic NMDA receptor in the mechanical hyperalgesia in diabetic rats","volume":"39","author":"Wang","year":"2017","journal-title":"Neurol. Res."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Matos-Perdomo, E., and Mach\u00edn, F. (2019). Nucleolar and Ribosomal DNA Structure under Stress: Yeast Lessons for Aging and Cancer. Cells, 8.","DOI":"10.3390\/cells8080779"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1089\/scd.2016.0325","article-title":"The Role of NMDA Receptors in Neural Stem Cell Proliferation and Differentiation","volume":"26","author":"Chakraborty","year":"2017","journal-title":"Stem Cells Dev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e003423","DOI":"10.1161\/CIRCHEARTFAILURE.116.003423","article-title":"Hypoxia-Inducible Factor-1\u03b1 Mediates Increased Sympathoexcitation via Glutamatergic N-Methyl-d-Aspartate Receptors in the Paraventricular Nucleus of Rats with Chronic Heart Failure","volume":"9","author":"Sharma","year":"2016","journal-title":"Circ. Heart Fail."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1152\/jn.01044.2006","article-title":"Modulation of NMDA Receptor Properties and Synaptic Transmission by the NR3A Subunit in Mouse Hippocampal and Cerebrocortical Neurons","volume":"99","author":"Tong","year":"2008","journal-title":"J. Neurophysiol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Hajd\u00fa, T., Juh\u00e1sz, T., Sz\u0171cs-Somogyi, C., R\u00e1cz, K., and Z\u00e1k\u00e1ny, R. (2018). NR1 and NR3B Composed Intranuclear N-methyl-d-aspartate Receptor Complexes in Human Melanoma Cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19071929"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1111\/j.1526-4637.2012.01488.x","article-title":"Epigenetics and the Transition from Acute to Chronic Pain","volume":"13","author":"Buchheit","year":"2012","journal-title":"Pain Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6133","DOI":"10.1007\/s12035-016-0156-0","article-title":"Epigenetic Regulation of SNAP25 Prevents Progressive Glutamate Excitotoxicty in Hypoxic CA3 Neurons","volume":"54","author":"Biswal","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1038\/s41598-018-19921-x","article-title":"The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia","volume":"8","author":"Vecino","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.bbi.2016.12.016","article-title":"Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels","volume":"61","author":"Noor","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s40478-019-0701-y","article-title":"Targeting the \u03b22-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure","volume":"7","author":"Sanchez","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.neuint.2011.10.018","article-title":"Exposure to novel environment is characterized by an interaction of D1\/NMDA receptors underlined by phosphorylation of the NMDA and AMPA receptor subunits and activation of ERK1\/2 signaling, leading to epigenetic changes and gene expression in rat hippocampus","volume":"60","author":"Sarantis","year":"2012","journal-title":"Neurochem. Int."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1007\/s00701-004-0281-9","article-title":"Differential effects of prolonged isoflurane anesthesia on plasma, extracellular, and CSF glutamate, neuronal activity, 125I-Mk801 NMDA receptor binding, and brain edema in traumatic brain-injured rats","volume":"146","author":"Stover","year":"2004","journal-title":"Acta Neurochir."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1111\/j.1471-4159.2005.03200.x","article-title":"The excitoprotective effect of N-methyl-d-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons","volume":"94","author":"Jiang","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/ptr.6239","article-title":"Genistein inhibits A\u03b225\u201335-induced SH-SY5Y cell damage by modulating the expression of apoptosis-related proteins and Ca2+ influx through ionotropic glutamate receptors","volume":"33","author":"Xu","year":"2019","journal-title":"Phytother. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1111\/j.1365-2249.2004.02563.x","article-title":"Excitatory amino acids, TNF-\u03b1, and chemokine levels in synovial fluids of patients with active arthropathies","volume":"137","author":"McNearney","year":"2004","journal-title":"Clin. Exp. Immunol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1046\/j.1523-1747.1999.00509.x","article-title":"Evidence for a Novel Glutamate-Mediated Signaling Pathway in Keratinocytes","volume":"112","author":"Genever","year":"1999","journal-title":"J. Investig. Dermatol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.pain.2004.08.005","article-title":"The protein tyrosine kinase inhibitor, genistein, decreases excitability of nociceptive neurons","volume":"112","author":"Liu","year":"2004","journal-title":"Pain"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13196\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:38:46Z","timestamp":1760128726000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13196"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,25]]},"references-count":97,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241713196"],"URL":"https:\/\/doi.org\/10.3390\/ijms241713196","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,25]]}}}