{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T14:18:40Z","timestamp":1774966720396,"version":"3.50.1"},"reference-count":29,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fibromyalgia (FM) is a chronic pain syndrome characterized by central sensitization, in which glutamatergic and purinergic signaling pathways are thought to play critical roles. This study aimed to evaluate the diagnostic potential of serum glutamate ionotropic receptor N-methyl-D-aspartate type subunit 1 (GRIN1), purinergic receptor P2X 1 (P2RX1), and purinergic receptor P2Y 2 (P2RY2) levels in patients with FM. A total of 93 newly diagnosed FM patients and 93 age- and sex-matched healthy controls were included in the study. Serum levels of GRIN1, P2RX1, and P2RY2 were measured using enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic performance of these biomarkers. ROC analysis demonstrated good diagnostic accuracy for all three biomarkers. The area under the curve (AUC) values were 0.817 for GRIN1, 0.778 for P2RX1, and 0.842 for P2RY2 (p &lt; 0.001 for all). At optimal cut-off values, GRIN1, P2RX1, and P2RY2 showed sensitivities of 91.4%, 78.5%, and 92.5%, and specificities of 72.00%, 75.3%, and 80.6%, respectively. Serum GRIN1, P2RX1, and P2RY2 levels exhibit strong diagnostic performance in FM and may serve as promising biomarkers reflecting altered glutamatergic and purinergic signaling in disease pathophysiology.<\/jats:p>","DOI":"10.3390\/ijms27073164","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T13:23:17Z","timestamp":1774963397000},"page":"3164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Serum Levels of Glutamatergic (GRIN1) and Purinergic (P2RX1\/P2RY2) Receptors in Patients with Fibromyalgia"],"prefix":"10.3390","volume":"27","author":[{"given":"Sevil Ceyhan","family":"Dogan","sequence":"first","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Sivas Cumhuriyet University, Sivas 58140, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00fclcihan Cinar","family":"Kaya","sequence":"additional","affiliation":[{"name":"Department of Medical Services and Techniques, Y\u0131ld\u0131zeli Vocational School, Medical Laboratory Techniques Program, Sivas Cumhuriyet University, Sivas 58140, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuhal","family":"Tuncbilek","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Processing Technologies Services, Y\u0131ld\u0131zeli Vocational School, Biochemistry Program, Sivas Cumhuriyet University, Sivas 58140, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6713-5888","authenticated-orcid":false,"given":"Mert","family":"Atas","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Sivas Cumhuriyet University, Sivas 58140, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7132-1325","authenticated-orcid":false,"given":"Ayca","family":"Tas","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Sivas Cumhuriyet University, Sivas 58140, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1001\/jama.2014.3266","article-title":"Fibromyalgia: A clinical review","volume":"311","author":"Clauw","year":"2014","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1007\/s11916-013-0356-5","article-title":"Worldwide epidemiology of fibromyalgia","volume":"17","author":"Queiroz","year":"2013","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s12016-015-8509-4","article-title":"Fibromyalgia: A critical and comprehensive review","volume":"49","author":"Borchers","year":"2015","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.berh.2011.02.005","article-title":"Central pain mechanisms in chronic pain states: Maybe it is all in their head","volume":"25","author":"Phillips","year":"2011","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/nrn3504","article-title":"NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease","volume":"14","author":"Paoletti","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1016\/j.pain.2010.09.030","article-title":"Central sensitization: Implications for the diagnosis and treatment of pain","volume":"152","author":"Woolf","year":"2011","journal-title":"Pain"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"D\u2019amico, R., Fusco, R., Siracusa, R., Impellizzeri, D., Peritore, A.F., Gugliandolo, E., Interdonato, L., Sforza, A.M., Crupi, R., and Cuzzocrea, S. (2021). Inhibition of P2X7 purinergic receptor ameliorates fibromyalgia syndrome by suppressing NLRP3 pathway. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126471"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s11481-025-10207-4","article-title":"Possible interaction of suramin with thalamic P2X receptors and NLRP3 inflammasome activation alleviates reserpine-induced fibromyalgia-like symptoms","volume":"20","author":"Mohamed","year":"2025","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_9","first-page":"920","article-title":"P2X receptors in health and disease","volume":"80","author":"Burnstock","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0031-6997(24)01373-5","article-title":"Receptors for purines and pyrimidines","volume":"50","author":"Ralevic","year":"1998","journal-title":"Pharmacol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Burnstock, G. (2017). Purinergic signalling: Therapeutic developments. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00661"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s11302-006-9045-8","article-title":"P2 receptors and chronic pain","volume":"3","author":"Inoue","year":"2007","journal-title":"Purinergic Signal."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"\u00dc\u00e7eyler, N., Kewenig, S., Kafke, W., Kittel-Schneider, S., and Sommer, C. (2014). Skin cytokine expression in patients with fibromyalgia syndrome is not different from controls. BMC Neurol., 14.","DOI":"10.1186\/s12883-014-0185-0"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1002\/wmts.62","article-title":"Coupling of P2Y receptors to G proteins and other signaling pathways","volume":"1","author":"Erb","year":"2012","journal-title":"Wiley Interdiscip. Rev. Membr. Transp. Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"176140","DOI":"10.1016\/j.ejphar.2023.176140","article-title":"Pregabalin inhibits purinergic P2Y2 receptor and TRPV4 to suppress astrocyte activation and relieve neuropathic pain","volume":"960","author":"Song","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"ref_16","first-page":"17","article-title":"Can aberrant spinal nociception be a marker of chronicity of pain in fibromyalgia syndrome?","volume":"706","author":"Tanwar","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Siracusa, R., Paola, R.D., Cuzzocrea, S., and Impellizzeri, D. (2021). Fibromyalgia: Pathogenesis, mechanisms, diagnosis and treatment options update. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083891"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Littlejohn, G., and Guymer, E. (2020). Key milestones contributing to the understanding of fibromyalgia mechanisms. Biomedicines, 8.","DOI":"10.3390\/biomedicines8070223"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/AJP.0000000000001085","article-title":"Central sensitization and small-fiber neuropathy in fibromyalgia","volume":"39","author":"Dumolard","year":"2023","journal-title":"Clin. J. Pain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1097\/PR9.0000000000000901","article-title":"Pain matters for central sensitization: sensory and psychological parameters in patients with fibromyalgia syndrome","volume":"6","author":"Rehm","year":"2021","journal-title":"Pain Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s10827-022-00826-8","article-title":"Thalamocortical bistable switch as a theoretical model of fibromyalgia pathogenesis inferred from a literature survey","volume":"50","author":"Demori","year":"2022","journal-title":"J. Comput. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1213\/01.ANE.0000081061.12235.55","article-title":"The role of NMDA receptors in pain","volume":"97","author":"Petrenko","year":"2003","journal-title":"Anesth. Analg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"116427","DOI":"10.1016\/j.bcp.2024.116427","article-title":"TFAP2A regulates GRIN1 in neuropathic pain","volume":"227","author":"Yuan","year":"2024","journal-title":"Biochem. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.pain.2010.06.037","article-title":"NMDA receptor changes and pain behavior","volume":"151","author":"Walder","year":"2010","journal-title":"Pain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.jpain.2008.09.013","article-title":"siRNA-mediated NMDA receptor knockdown reduces pain","volume":"10","author":"Garraway","year":"2009","journal-title":"J. Pain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.brainresrev.2009.11.003","article-title":"Pain and purinergic signaling","volume":"63","author":"Tsuda","year":"2010","journal-title":"Brain Res. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41421-025-00797-x","article-title":"Structural insight into P2Y2 receptor activation","volume":"11","author":"Lan","year":"2025","journal-title":"Cell Discov."},{"key":"ref_28","first-page":"21","article-title":"Inhibition of G protein-coupled P2Y2 receptor induced analgesia in a rat model of trigeminal neuropathic pain","volume":"18","author":"Li","year":"2014","journal-title":"Mol. Pain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.semarthrit.2016.08.012","article-title":"2016 revisions to fibromyalgia diagnostic criteria","volume":"46","author":"Wolfe","year":"2016","journal-title":"Semin. Arthritis Rheum."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/3164\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T13:27:11Z","timestamp":1774963631000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/3164"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":29,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27073164"],"URL":"https:\/\/doi.org\/10.3390\/ijms27073164","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,31]]}}}