{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:49:12Z","timestamp":1791434952977,"version":"4.3.3"},"reference-count":36,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J of Neuroscience"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Migraine headache prevalence is lower in patients with diabetes, but the underlying mechanisms remains unclear. This study explored the influences of hyperglycemia, insulin and insulin receptor (IR)\/insulin\u2010like growth factor 1 receptor (IGF\u20101R)\u2013related signalling on migraine\u2010related mechanisms in in\u00a0vivo and ex\u00a0vivo rat models. In in\u00a0vivo experiments, migraine\u2010relevant responses were induced by systemic injection of nitroglycerin (NTG), whereas hyperglycemia was induced by streptozotocin (STZ). The effects of hyperglycemia, insulin and the dual IR\/IGF\u20101R inhibitor BMS\u2010754807 were investigated. In ex\u00a0vivo experiments, the effects of insulin and BMS on basal and capsaicin\u2010induced calcitonin gene\u2010related peptide (CGRP) releases from migraine\u2010associated tissues (peripheral meningeal afferents and trigeminal ganglion, and central brainstem trigeminal nucleus) were directly tested. Mechanical hyperalgesia was evaluated by von\u2010Frey, CGRP and c\u2010Fos levels by ELISA and meningeal mast cells by toluidine\u2010blue staining. In in\u00a0vivo NTG group, insulin further lowered the pain threshold and further enhanced CGRP and c\u2010fos concentrations in trigeminal tissues and mast cell activation in the meninges. Hyperglycemia alone or in the NTG\u2010treated group did not change these parameters. In ex\u00a0vivo experiments, direct administration of insulin stimulated CGRP release in meningeal and trigeminal ganglion, but not trigeminal nucleus, tissues and further enhanced capsaicin\u2010stimulated CGRP release, confirming the in\u00a0vivo effects. The in\u00a0vivo and ex\u00a0vivo effects of insulin were reversed by BMS. Hyperglycemia did not modify the NTG\u2010induced responses. However, insulin facilitates migraine\u2010related responses by enhancing trigeminal CGRP signalling and meningeal mast cell activation through IR and\/or IGF\u20101R\u2010related signalling. Modulation of insulin\u2010responsive IR\/IGF\u20101R\u2013related signalling within the trigeminovascular system may represent a potential target for future therapeutic strategies.<\/jats:p>","DOI":"10.1111\/ejn.70705","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T03:50:43Z","timestamp":1791431443000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Insulin Enhances Nitroglycerin\u2010Induced Hyperalgesia Through Insulin\u2010Responsive Receptor Signalling Involving the Trigeminovascular System and Meningeal Mast Cells"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7035-3336","authenticated-orcid":false,"given":"Ibrahim Ethem","family":"Torun","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine Bolu Abant Izzet Baysal University  Bolu 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