{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:25:02Z","timestamp":1791473102139,"version":"4.3.4"},"reference-count":106,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T00:00:00Z","timestamp":1741996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["20-15-00100"],"award-info":[{"award-number":["20-15-00100"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Elevated levels of homocysteine in the blood plasma (hyperhomocysteinemia, HHCY) positively correlate with migraine symptoms in patients. Experimental studies show a higher sensitivity of rats with prenatal HHCY (pHHCY) to migraine symptoms like allodynia, photophobia, anxiety, and a higher excitability of meningeal trigeminal afferents. In the present study, the roles of purinergic mechanisms in the homocysteine-induced hyperexcitability of the trigeminal ganglion (TG) system using electrophysiological recordings from the trigeminal nerve, Ca2+ imaging of cells isolated from TG, and mast cell staining in meninges were investigated. Experiments were performed using rats with pHHCY born from females fed with a high-methionine-containing diet before and during pregnancy. Firstly, we found that lower concentrations of 4-aminopyridine, a K+-channel blocker, were able to induce an increase in the nociceptive activity of trigeminal afferents, supporting the hypothesis of the higher excitability of the trigeminal nerve of rats with pHHCY. Trigeminal afferents of rats with pHHCY were more sensitive to the exogenous application of the nonspecific agonist of purinergic ATP receptors. In neurons and satellite glial cells of TG of rats with pHHCY ATP, ADP (an agonist of metabotropic P2Y receptors) and BzATP (an agonist of ionotropic P2X with especially high potency for the P2X7 receptor) induced larger Ca2+ transients. The incubation of TG neurons in homocysteine for 24 h increased the ratio of neurons responding simultaneously to ATP and capsaicin. Moreover, rats with pHHCY exhibit a higher rate of degranulation of mast cells and increased response to the agonist of the P2X7 receptor BzATP application. In addition, higher levels of calcitonin gene-related peptide (CGRP) were found in rats with pHHCY. Our results suggest that chronic elevated levels of homocysteine induce the upregulation of ionotropic or metabotropic ATP receptors in neurons, satellite glial cells, and mast cells, which further provide inflammatory conditions and the sensitization of peripheral afferents underlying pain.<\/jats:p>","DOI":"10.3390\/biom15030419","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T07:49:57Z","timestamp":1742197797000},"page":"419","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Role of Purinergic Mechanisms in the Excitability of Trigeminal Afferents of Rats with Prenatal Hyperhomocysteinemia"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2045-5294","authenticated-orcid":false,"given":"Elizaveta","family":"Ermakova","sequence":"first","affiliation":[{"name":"Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1507-6120","authenticated-orcid":false,"given":"Svetlana","family":"Svitko","sequence":"additional","affiliation":[{"name":"Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alsu","family":"Kabirova","sequence":"additional","affiliation":[{"name":"Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Egor","family":"Nevsky","sequence":"additional","affiliation":[{"name":"Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Yakovleva","sequence":"additional","affiliation":[{"name":"Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Gilizhdinova","sequence":"additional","affiliation":[{"name":"Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kseniia","family":"Shaidullova","sequence":"additional","affiliation":[{"name":"Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Hermann","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Salzburg, Hellbrunnerstr. 34, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5412-2204","authenticated-orcid":false,"given":"Guzel","family":"Sitdikova","sequence":"additional","affiliation":[{"name":"Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s10545-006-0106-5","article-title":"Homocysteine Metabolism, Hyperhomocysteinaemia and Vascular Disease: An Overview","volume":"29","author":"Castro","year":"2006","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2506S","DOI":"10.1093\/jn\/nxaa134","article-title":"Lessons Learned from Inherited Metabolic Disorders of Sulfur-Containing Amino Acids Metabolism","volume":"150","author":"Stabler","year":"2020","journal-title":"J. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Nieraad, H., Pannwitz, N., Bruin, N.D., Geisslinger, G., and Till, U. (2021). MetabolicRole and Animal Studies with a Focus on Cognitive Performance and Decline\u2014A Review. Biomolecules, 11.","DOI":"10.3390\/biom11101546"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Marroncini, G., Martinelli, S., Menchetti, S., Bombardiere, F., and Martelli, F.S. (2024). Hyperhomocysteinemia and Disease-Is 10 \u039cmol\/L a Suitable New Threshold Limit?. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202410.0319.v1"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"\u0160kovierov\u00e1, H., Vidomanov\u00e1, E., Mahmood, S., Sopkov\u00e1, J., Drgov\u00e1, A., \u010cerve\u0148ov\u00e1, T., Hala\u0161ov\u00e1, E., and Lehotsk\u00fd, J. (2016). The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17101733"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"668","DOI":"10.3945\/ajcn.112.044545","article-title":"Common Genetic Loci Influencing Plasma Homocysteine Concentrations and Their Effect on Risk of Coronary Artery Disease","volume":"98","author":"Pare","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_7","first-page":"15","article-title":"Hyperhomocysteinemia as a Risk Factor for the Neuronal System Disorders","volume":"65","author":"Petras","year":"2014","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/bcpt.12424","article-title":"Hyperhomocysteinemia: Impact on Neurodegenerative Diseases","volume":"117","author":"Sharma","year":"2015","journal-title":"Basic. Clin. Pharmacol. Toxicol."},{"key":"ref_9","first-page":"686","article-title":"Neurotoxic and Neuroprotective Effects of Homocysteine and Hydrogen Sulfide","volume":"160","author":"Sitdikova","year":"2018","journal-title":"Uchenye Zap. Kazan. Univ. Seriya Estestv. Nauk."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Tinelli, C., Di Pino, A., Ficulle, E., Marcelli, S., and Feligioni, M. (2019). Hyperhomocysteinemia as a Risk Factor and Potential Nutraceutical Target for Certain Pathologies. Front. Nutr., 6.","DOI":"10.3389\/fnut.2019.00049"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sitdikova, G., and Hermann, A. (2023). Homocysteine: Biochemistry, Molecular Biology, and Role in Disease 2021. Biomolecules, 13.","DOI":"10.3390\/biom13071111"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1073\/pnas.92.5.1585","article-title":"Mice Deficient in Cystathionine Beta-Synthase: Animal Models for Mild and Severe Homocyst(e)Inemia","volume":"92","author":"Watanabe","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2015.04.067","article-title":"MTHFR Deficiency or Reduced Intake of Folate or Choline in Pregnant Mice Results in Impaired Short-Term Memory and Increased Apoptosis in the Hippocampus of Wild-Type Offspring","volume":"300","author":"Jadavji","year":"2015","journal-title":"Neuroscience"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Yakovleva, O., Bogatova, K., Mukhtarova, R., Yakovlev, A., Shakhmatova, V., Gerasimova, E., Ziyatdinova, G., Hermann, A., and Sitdikova, G. (2020). Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress. Biomolecules, 10.","DOI":"10.3390\/biom10070995"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1007\/s12640-020-00233-w","article-title":"Maternal Hyperhomocysteinemia Induces Neuroinflammation and Neuronal Death in the Rat Offspring Cortex","volume":"38","author":"Shcherbitskaia","year":"2020","journal-title":"Neurotox. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vasilev, D.S., Shcherbitskaia, A.D., Tumanova, N.L., Mikhel, A.V., Milyutina, Y.P., Kovalenko, A.A., Dubrovskaya, N.M., Inozemtseva, D.B., Zalozniaia, I.V., and Arutjunyan, A.V. (2023). Maternal Hyperhomocysteinemia Disturbs the Mechanisms of Embryonic Brain Development and Its Maturation in Early Postnatal Ontogenesis. Cells, 12.","DOI":"10.3390\/cells12010189"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gerasimova, E., Enikeev, D., Yakovlev, A., Zakharov, A., and Sitdikova, G. (2024). Chronic Hyperhomocysteinemia Impairs CSD Propagation and Induces Cortical Damage in a Rat Model of Migraine with Aura. Biomolecules, 14.","DOI":"10.3390\/biom14111379"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s10072-008-0917-2","article-title":"Homocysteine Plasma Levels in Patients with Migraine with Aura","volume":"29","author":"Moschiano","year":"2008","journal-title":"Neurol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.cca.2014.02.028","article-title":"Homocysteine and Migraine. A Narrative Review","volume":"433","author":"Lippi","year":"2014","journal-title":"Clin. Chim. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/ncn3.12128","article-title":"Migraine Homocysteine-related: Old and New Mechanisms","volume":"5","author":"Cacciapuoti","year":"2017","journal-title":"Neurol. Clin. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1111\/head.13540","article-title":"Effects of MTHFR C677T and A1298C Polymorphisms on Migraine Susceptibility: A Meta-Analysis of 26 Studies","volume":"59","author":"Liu","year":"2019","journal-title":"Headache"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1111\/head.13892","article-title":"Serum Homocysteine, Pyridoxine, Folate, and Vitamin B12 Levels in Migraine: Systematic Review and Meta-analysis","volume":"60","author":"Liampas","year":"2020","journal-title":"Headache"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113324","DOI":"10.1016\/j.bbr.2021.113324","article-title":"Hyperhomocysteinemia Increases Susceptibility to Cortical Spreading Depression Associated with Photophobia, Mechanical Allodynia, and Anxiety in Rats","volume":"409","author":"Gerasimova","year":"2021","journal-title":"Behav. Brain Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gerasimova, E., Yakovleva, O., Enikeev, D., Bogatova, K., Hermann, A., Giniatullin, R., and Sitdikova, G. (2022). Hyperhomocysteinemia Increases Cortical Excitability and Aggravates Mechanical Hyperalgesia and Anxiety in a Nitroglycerine-Induced Migraine Model in Rats. Biomolecules, 12.","DOI":"10.3390\/biom12050735"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Demartini, C., Francavilla, M., Zanaboni, A.M., Facchetti, S., De Icco, R., Martinelli, D., Allena, M., Greco, R., and Tassorelli, C. (2023). Biomarkers of Migraine: An Integrated Evaluation of Preclinical and Clinical Findings. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065334"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/bs.pmbts.2015.01.001","article-title":"Meningeal Afferent Signaling and the Pathophysiology of Migraine","volume":"131","author":"Moy","year":"2015","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/384560a0","article-title":"Sensitization of Meningeal Sensory Neurons and the Origin of Headaches","volume":"384","author":"Strassman","year":"1996","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1152\/jn.1997.77.1.299","article-title":"Primary Afferent Neurons Innervating Guinea Pig Dura","volume":"77","author":"Bove","year":"1997","journal-title":"J. Neurophysiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1152\/jn.00029.2002","article-title":"Mechanical Response Properties of A and C Primary Afferent Neurons Innervating the Rat Intracranial Dura","volume":"88","author":"Levy","year":"2002","journal-title":"J. Neurophysiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1152\/jn.01293.2005","article-title":"Response Properties of Dural Nociceptors in Relation to Headache","volume":"95","author":"Strassman","year":"2006","journal-title":"J. Neurophysiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s10194-022-01535-4","article-title":"Role of ATP in Migraine Mechanisms: Focus on P2X3 Receptors","volume":"24","author":"Giniatullin","year":"2023","journal-title":"J. Headache Pain."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s11302-016-9521-8","article-title":"Nucleotide Homeo-Stasis and Purinergic Nociceptive Signaling in Rat Meninges","volume":"12","author":"Yegutkin","year":"2016","journal-title":"Purinergic Signal."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Koroleva, K., Gafurov, O., Guselnikova, V., Nurkhametova, D., Giniatullina, R., Sitdikova, G., Mattila, O.S., Lindsberg, P.J., Malm, T.M., and Giniatullin, R. (2019). Meningeal Mast Cells Contribute to ATP-Induced Nociceptive Firing in Trigeminal Nerve Terminals: Direct and Indirect Purinergic Mechanisms Triggering Migraine Pain. Front. Cell. Neurosci., 13.","DOI":"10.3389\/fncel.2019.00195"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.neuropharm.2016.12.024","article-title":"Serotonergic Mechanisms of Trigeminal Meningeal Nociception: Implications for Migraine Pain","volume":"116","author":"Kilinc","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7878","DOI":"10.1523\/JNEUROSCI.6053-09.2010","article-title":"Ionic Mechanisms Underlying Inflammatory Mediator-Induced Sensitization of Dural Afferents","volume":"30","author":"Vaughn","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6163","DOI":"10.1523\/JNEUROSCI.0647-06.2006","article-title":"Delayed Upregulation of ATP P2X3 Receptors of Trigeminal Sensory Neurons by Calcitonin Gene-Related Peptide","volume":"26","author":"Fabbretti","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s11302-015-9453-8","article-title":"The Role of Purinergic Signaling in the Etiology of Migraine and Novel Antimigraine Treatment","volume":"11","author":"Czarnecka","year":"2015","journal-title":"Purinergic Signal."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/s41582-019-0216-y","article-title":"Does Inflammation Have a Role in Migraine?","volume":"15","author":"Edvinsson","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s12035-008-8020-5","article-title":"Molecular Mechanisms of Sensitization of Pain-Transducing P2X3 Receptors by the Migraine Mediators CGRP and NGF","volume":"37","author":"Giniatullin","year":"2008","journal-title":"Mol. Neurobiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1007\/s11064-012-0769-2","article-title":"Chronic Hyperhomocysteinemia Increases Inflammatory Markers in Hippocampus and Serum of Rats","volume":"37","author":"Ferreira","year":"2012","journal-title":"Neurochem. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s12035-014-8660-6","article-title":"Mild Hyperhomocysteinemia Increases Brain Acetyl- Cholinesterase and Proinflflammatory Cytokine Levels in Different Tissues","volume":"50","author":"Scherer","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Elsherbiny, N.M., Sharma, I., Kira, D., Alhusban, S., Samra, Y.A., Jadeja, R., Martin, P., Al-Shabrawey, M., and Tawfik, A. (2020). Homocysteine Induces Inflammation in Retina and Brain. Biomolecules, 10.","DOI":"10.3390\/biom10030393"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jphs.2024.05.001","article-title":"H2S Prevents the Disruption of the Blood-Brain Barrier in Rats with Prenatal Hyperhomocysteinemia","volume":"155","author":"Yakovlev","year":"2024","journal-title":"J. Pharmacol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.ijdevneu.2011.06.004","article-title":"Development of an Animal Model for Chronic Mild Hyperhomocysteinemia and Its Response to Oxidative Damage","volume":"29","author":"Scherer","year":"2011","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1007\/s12640-017-9847-1","article-title":"Chronic Mild Hyperhomocysteinemia Alters Inflammatory and Oxidative\/Nitrative Status and Causes Protein\/DNA Damage, as Well as Ultrastructural Changes in Cerebral Cortex: Is Acetylsalicylic Acid Neuroprotective?","volume":"33","author":"Siebert","year":"2018","journal-title":"Neurotox. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4517","DOI":"10.1007\/s12035-022-02871-x","article-title":"Rivastigmine Reverses the Decrease in Synapsin and Memory Caused by Homocysteine: Is There Relation to Inflammation?","volume":"59","author":"Silveira","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s11010-017-3026-9","article-title":"Toll-like Receptor 4 Mediates Vascular Remodeling in Hyperhomocysteinemia","volume":"433","author":"Familtseva","year":"2017","journal-title":"Mol. Cell. Biochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s11302-015-9464-5","article-title":"Pathological Concentrations of Homocysteine Increases IL-1\u03b2 Production in Macrophages in a P2X7, NF-\u0138B, and Erk-Dependent Manner","volume":"11","author":"Zanin","year":"2015","journal-title":"Purinergic Signal."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s11010-015-2335-0","article-title":"Protective Effects of Genistein in Homocysteine-Induced Endothelial Cell Inflammatory Injury","volume":"403","author":"Han","year":"2015","journal-title":"Mol. Cell. Biochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"12560","DOI":"10.3390\/ijms160612560","article-title":"Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter","volume":"16","author":"Li","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2746873","DOI":"10.1155\/2018\/2746873","article-title":"Hydrogen Sulfide Ameliorates Developmental Impairments of Rat Offspring with Prenatal Hyperhomocysteinemia","volume":"2018","author":"Yakovleva","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1146\/annurev-neuro-080422-105509","article-title":"Meningeal Mechanisms and the Migraine Connection","volume":"46","author":"Levy","year":"2023","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_53","first-page":"564","article-title":"Dural Administration of Inflammatory Soup or Complete Freund\u2019s Adjuvant Induces Activation and Inflammatory Response in the Rat Trigeminal Ganglion","volume":"16","author":"Haanes","year":"2015","journal-title":"J. Headache Pain."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s00540-018-2579-4","article-title":"Roles of Inflammation, Neurogenic Inflammation, and Neuroinflammation in Pain","volume":"33","author":"Matsuda","year":"2019","journal-title":"J. Anesth."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1111\/head.14710","article-title":"Implications of High Homocysteine Levels in Migraine Pain: An Experimental Study of the Excitability of Peripheral Meningeal Afferents in Rats with Hyperhomocysteinemia","volume":"64","author":"Ermakova","year":"2024","journal-title":"Headache"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s12668-016-0326-6","article-title":"Effects of Maternal Hyperhomocysteinemia on the Early Physical Development and Neurobehavioral Maturation of Rat Offspring","volume":"7","author":"Gerasimova","year":"2016","journal-title":"BioNanoScience"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Koroleva, K., Mustafina, A., Yakovlev, A., Hermann, A., Giniatullin, R., and Sitdikova, G. (2017). Receptor Mechanisms Mediating the Pro-Nociceptive Action of Hydrogen Sulfide in Rat Trigeminal Neurons and Meningeal Afferents. Front. Cell. Neurosci., 11.","DOI":"10.3389\/fncel.2017.00226"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Koroleva, K., Ermakova, E., Mustafina, A., Giniatullina, R., Giniatullin, R., and Sitdikova, G. (2020). Protective Effects of Hydrogen Sulfide against the ATP-Induced Meningeal Nociception. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.00266"},{"key":"ref_59","first-page":"70","article-title":"Method for simultaneous visualization of mast cells and nerve terminals in the rodent thymus","volume":"145","author":"Sukhorukova","year":"2014","journal-title":"Morfologiia"},{"key":"ref_60","first-page":"e42210","article-title":"Parasympathetic Cholinergic and Peptidergic Mechanisms of Trigeminal Pain","volume":"7","author":"Mikhailov","year":"2017","journal-title":"Anesth. Pain Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1007\/s11055-020-00983-2","article-title":"Mast Cell Mediators as Pain Triggers in Migraine: Comparison of Histamine and Serotonin in the Activation of Primary Afferents in the Meninges in Rats","volume":"50","author":"Nurkhametova","year":"2020","journal-title":"Neurosci. Behav. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1111\/j.1476-5381.2010.00879.x","article-title":"Matching Models to Data: A Receptor Pharmacologist\u2019s Guide","volume":"161","author":"Hall","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1111\/j.1468-2982.2007.01342.x","article-title":"Migraine Aura Status and Hyperhomocysteinaemia","volume":"27","author":"Cupini","year":"2007","journal-title":"Cephalalgia"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1111\/j.1526-4610.2010.01713.x","article-title":"A Remarkable Increase in Total Homocysteine Concentrations in the CSF of Migraine Patients with Aura","volume":"50","author":"Isobe","year":"2010","journal-title":"Headache"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5923","DOI":"10.1073\/pnas.94.11.5923","article-title":"Neurotoxicity Associated with Dual Actions of Homocysteine at the N-Methyl-d-Aspartate Receptor","volume":"94","author":"Lipton","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6920","DOI":"10.1523\/JNEUROSCI.20-18-06920.2000","article-title":"Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity","volume":"20","author":"Kruman","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1038\/jcbfm.2013.113","article-title":"Regenerative Glutamate Release by Presynaptic NMDA Receptors Contributes to Spreading Depression","volume":"33","author":"Zhou","year":"2013","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.bbrc.2018.10.140","article-title":"High Sensitivity of Cerebellar Neurons to Homocysteine Is Determined by Expression of GluN2C and GluN2D Subunits of NMDA Receptors","volume":"506","author":"Sibarov","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1007\/s12035-015-9212-4","article-title":"Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer\u2019s Disease-like Pathology, Blood-Brain Barrier Disruption, and Synaptic Disorder","volume":"53","author":"Kamat","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Zemel, B.M., Ritter, D.M., Covarrubias, M., and Muqeem, T. (2018). A-Type KV Channels in Dorsal Root Ganglion Neurons: Diversity, Function, and Dysfunction. Front. Mol. Neurosci., 11.","DOI":"10.3389\/fnmol.2018.00253"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1744806917750995","DOI":"10.1177\/1744806917750995","article-title":"Down-Regulation of Kv4.3 Channels and a-Type K+ Currents in V2 Trigeminal Ganglion Neurons of Rats Following Oxaliplatin Treatment","volume":"14","author":"Ling","year":"2018","journal-title":"Mol. Pain"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"30","DOI":"10.2174\/1874467211003010030","article-title":"The Roles of ID, IA and IK in the Electrophysiological Functions of Small-Diameter Rat Trigeminal Ganglion Neurons","volume":"3","author":"Matsumoto","year":"2010","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"9855","DOI":"10.1523\/JNEUROSCI.0604-07.2007","article-title":"Reduced Expression of A-Type Potassium Channels in Primary Sensory Neurons Induces Mechanical Hypersensitivity","volume":"27","author":"Chien","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.neures.2012.10.003","article-title":"Iontophoretic Application of an A-Type Potassium Channel Blocker to the Trigeminal Ganglion Neurons Enhances the Excitability of A\u03b4- and C-Neurons Innervating the Temporomandibular Joint in Rats","volume":"74","author":"Hara","year":"2012","journal-title":"Neurosci. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.ejpain.2007.04.005","article-title":"Temporomandibular Joint Inflammation Decreases the Voltage-Gated K+ Channel Subtype 1.4-Immunoreactivity of Trigeminal Ganglion Neurons in Rats","volume":"12","author":"Takeda","year":"2008","journal-title":"Eur. J. Pain."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.neuroscience.2007.01.051","article-title":"Sex-Related Differences in NMDA-Evoked Rat Masseter Muscle Afferent Discharge Result from Estrogen-Mediated Modulation of Peripheral NMDA Receptor Activity","volume":"146","author":"Dong","year":"2007","journal-title":"Neuroscience"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ejpain.2010.07.001","article-title":"Peripheral N-Methyl-d-Aspartate Receptors Contribute to Mechanical Hypersensitivity in a Rat Model of Inflflammatorytemporomandibular Joint Pain","volume":"15","author":"Ivanusicl","year":"2011","journal-title":"Eur. J. Pain."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1152\/jn.00809.2012","article-title":"Homocysteine Reduces NMDAR Desensitization and Differentially Modulates Peak Amplitude of NMDAR Currents, Depending on GluN2 Subunit Composition","volume":"110","author":"Bolton","year":"2013","journal-title":"J. Neurophysiol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Sibarov, D.A., Abushik, P.A., Giniatullin, R., and Antonov, S.M. (2016). GluN2A Subunit-Containing NMDA Receptors Are the Preferential Neuronal Targets of Homocysteine. Front. Cell. Neurosci., 10.","DOI":"10.3389\/fncel.2016.00246"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Guerrero-Toro, C., Koroleva, K., Ermakova, E., Gafurov, O., Abushik, P., Tavi, P., Sitdikova, G., and Giniatullin, R. (2022). Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031529"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Giniatullin, R., and Nistri, A. (2013). Desensitization Properties of P2X3 Receptors Shaping Pain Signaling. Front. Cell. Neurosci., 7.","DOI":"10.3389\/fncel.2013.00245"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1113\/jphysiol.2003.048587","article-title":"P2X3 Receptors and Peripheral Pain Mechanisms","volume":"554","author":"North","year":"2004","journal-title":"J. Physiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1111\/bph.13957","article-title":"P2X Receptor Channels in Chronic Pain Pathways","volume":"175","author":"Bernier","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.archoralbio.2018.08.012","article-title":"The Transient Receptor Potential Cation Channel Subfamily V Members 1 and 2, P2X Purinoceptor 3 and Calcitonin Gene-Related Peptide in Sensory Neurons of the Rat Trigeminal Ganglion, Innervating the Periosteum, Masseter Muscle and Facial Skin","volume":"96","author":"Sato","year":"2018","journal-title":"Arch. Oral Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s11011-010-9188-8","article-title":"Increased Inflammatory Markers in Brain and Blood of Rats Subjected to Acute Homocysteine Administration","volume":"25","author":"Ferreira","year":"2010","journal-title":"Metab. Brain Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.bbr.2019.01.039","article-title":"Attenuation of Hyperhomocysteinemia Induced Vascular Dementia by Sodium Orthovanadate Perhaps via PTP1B: Pertinent Downstream Outcomes","volume":"364","author":"Kumar","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1134\/S181971242203014X","article-title":"Levels of Protein Carbonylation and Activity of Proteases in the Brain of Newborn Rats with Prenatal Hyperhomocysteinemia","volume":"16","author":"Yakovlev","year":"2022","journal-title":"Neurochem. J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1182\/blood-2005-06-2506","article-title":"Elevated Levels of Homocysteine Compromise Blood-Brain Barrier Integrity in Mice","volume":"107","author":"Kamath","year":"2006","journal-title":"Blood"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1182\/blood-2011-02-338269","article-title":"Hyperhomocysteinemia Increases Permeability of the Blood-Brain Barrier by NMDA Receptor-Dependent Regulation of Adherens and Tight Junctions","volume":"118","author":"Beard","year":"2011","journal-title":"Blood"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1080\/00207454.2020.1860967","article-title":"Hydrogen Sulfide Attenuates Hyperhomocysteinemia-Induced Blood-Brain Barrier Permeability by Inhibiting MMP-9","volume":"132","author":"Kumar","year":"2022","journal-title":"Int. J. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s12035-007-0033-y","article-title":"P2X3 Receptor Involvement in Pain States","volume":"36","author":"Wirkner","year":"2007","journal-title":"Mol. Neurobiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.neuroscience.2006.09.035","article-title":"Localization of P2X2 and P2X3 Receptors in Rat Trigeminal Ganglion Neurons","volume":"144","author":"Staikopoulos","year":"2007","journal-title":"Neuroscience"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s00702-020-02161-7","article-title":"Cross-Talk Signaling in the Trigeminal Ganglion: Role of Neuropeptides and Other Mediators","volume":"127","author":"Messlinger","year":"2020","journal-title":"J. Neural Transm."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.pain.2005.01.002","article-title":"Disruption of the P2X7 Purinoceptor Gene Abolishes Chronic Inflammatory and Neuropathic Pain","volume":"114","author":"Chessell","year":"2005","journal-title":"Pain"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Nurkhametova, D., Siniavin, A., Streltsova, M., Kudryavtsev, D., Kudryavtsev, I., Giniatullina, R., Tsetlin, V., Malm, T., and Giniatullin, R. (2020). Does Cholinergic Stimulation Affect the P2X7 Receptor-Mediated Dye Uptake in Mast Cells and Macrophages?. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.548376"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3638","DOI":"10.1523\/JNEUROSCI.6440-10.2011","article-title":"Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron\/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Cav2.1 Knock-in Mice: Implications for Basic Mechanisms of Migraine Pain","volume":"31","author":"Ceruti","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Dux, M., Rosta, J., and Messlinger, K. (2020). TRP Channels in the Focus of Trigeminal Nociceptor Sensitization Contributing to Primary Headaches. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010342"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ejphar.2013.01.078","article-title":"Purinergic Mechanisms and Pain\u2014An Update","volume":"716","author":"Burnstock","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Zhang, X., and Li, G. (2019). P2Y Receptors in Neuropathic Pain. Pharmacol. Biochem. Behav., 186.","DOI":"10.1016\/j.pbb.2019.172788"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"18743","DOI":"10.1074\/jbc.M800296200","article-title":"Mechanisms Mediating the Enhanced Gene Transcription of P2X3 Receptor by Calcitonin Gene-Related Peptide in Trigeminal Sensory Neurons","volume":"283","author":"Simonetti","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1038\/35039526","article-title":"Warm-Coding Deficits and Aberrant Inflammatory Pain in Mice Lacking P2X3 Receptors","volume":"407","author":"Souslova","year":"2000","journal-title":"Nature"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/ana.410330109","article-title":"The Trigeminovascular System and Migraine: Studies Characterizing Cerebrovascular and Neuropeptide Changes Seen in Humans and Cats","volume":"33","author":"Goadsby","year":"1993","journal-title":"Ann. Neurol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1212\/WNL.0b013e3182a6cb72","article-title":"Interictal Increase of CGRP Levels in Peripheral Blood as a Biomarker for Chronic Migraine","volume":"81","author":"Larrosa","year":"2013","journal-title":"Neurology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1111\/head.13529","article-title":"CGRP and the Trigeminal System in Migraine","volume":"59","author":"Iyengar","year":"2019","journal-title":"Headache"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Koyuncu Irmak, D., Kilinc, E., and Tore, F. (2019). Shared Fate of Meningeal Mast Cells and Sensory Neurons in Migraine. Front. Cell. Neurosci., 13.","DOI":"10.3389\/fncel.2019.00136"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"174480692311813","DOI":"10.1177\/17448069231181358","article-title":"Roles of Mast Cells and Their Interactions with the Trigeminal Nerve in Migraine Headache","volume":"19","author":"Guan","year":"2023","journal-title":"Mol. Pain"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/3\/419\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:54:20Z","timestamp":1760028860000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/3\/419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,15]]},"references-count":106,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["biom15030419"],"URL":"https:\/\/doi.org\/10.3390\/biom15030419","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,15]]}}}