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Here, we characterize a hypothalamic\u2010trigeminal pathway involved in the regulation of migraine\u2010like allodynia. Using a combination of monosynaptic circuit, fiber photometry\u2010based calcium imaging, and behavioral assays in a nitroglycerin (NTG)\u2010induced murine model, we observed hyperactivity in corticotropin\u2010releasing factor (CRF)\u2010expressing neurons within the hypothalamic paraventricular nucleus (PVN). Activation or inhibition of PVN\n                    <jats:sup>CRF<\/jats:sup>\n                    neurons mimicked or blocked migraine\u2010like allodynia, respectively. These PVN\n                    <jats:sup>CRF<\/jats:sup>\n                    neurons modulated migraine\u2010like allodynia by exciting glutamatergic neurons in the spinal trigeminal nucleus caudalis (SP5C). Furthermore, employing a CRF neurotransmitter fluorescent sensor, neuropharmacology, and electrophysiological recordings, we revealed that PVN\n                    <jats:sup>CRF<\/jats:sup>\n                    neurons excessively release CRF neuropeptides onto SP5C\n                    <jats:sup>Glu<\/jats:sup>\n                    neurons during migraine\u2010like conditions. This led to hyperactivation of corticotropin\u2010releasing factor receptor type 2 (CRFR2), but not type 1 (CRFR1), resulting in hyperalgesia. Blockade of CRFR2 within the SP5C significantly alleviated migraine\u2010like allodynia. Complementing these findings, clinical functional magnetic resonance imaging (fMRI) of migraine patients indicated structural and functional alterations in PVN and SP5C regions associated with this pathway. Collectively, our results uncover a previously unappreciated PVN\n                    <jats:sup>CRF<\/jats:sup>\n                    \u2010SP5C\n                    <jats:sup>Glu<\/jats:sup>\n                    pathway in migraine\u2010like allodynia, providing novel insights into the neurobiology of migraine and identifying potential therapeutic targets.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520530","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T03:06:18Z","timestamp":1773025578000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PVN\n                    <sup>CRF<\/sup>\n                    Neurons Regulate Migraine\u2010Like Allodynia by Activating CRFR2 on Spinal Trigeminal Caudalis Glutamatergic Neurons"],"prefix":"10.1002","volume":"13","author":[{"given":"Jiang","family":"Bian","sequence":"first","affiliation":[{"name":"Neuropsychiatry Research Institute, Basic School of Medicine The Affiliated Hospital of Qingdao University Qingdao University Qingdao China"},{"name":"Department of Anesthesiology Panzhihua Central Hospital Panzhihua China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Long","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery General Surgery Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Panzhihua Central Hospital Panzhihua China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Radiology Henan Provincial People's Hospital &amp; State Key Laboratory of Metabolic Dysregulation &amp; Prevention and Treatment of Esophageal Cancer Zhengzhou University  Zhengzhou Henan 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Radiology Henan Provincial People's Hospital &amp; State Key Laboratory of Metabolic Dysregulation &amp; Prevention and Treatment of Esophageal Cancer Zhengzhou University  Zhengzhou Henan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010Juan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiology Henan Provincial People's Hospital &amp; State Key Laboratory of Metabolic Dysregulation &amp; Prevention and Treatment of Esophageal Cancer Zhengzhou University  Zhengzhou Henan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming\u2010Wei","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology Karolinska Institute  Stockholm Sweden"},{"name":"Breast Disease Center The First Affiliated Hospital, Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Neuropsychiatry Research Institute, Basic School of Medicine The Affiliated Hospital of Qingdao University Qingdao University Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4260-0374","authenticated-orcid":false,"given":"Xu","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Radiology Henan Provincial People's Hospital &amp; State Key Laboratory of Metabolic Dysregulation &amp; Prevention and Treatment of Esophageal Cancer Zhengzhou University  Zhengzhou Henan China"},{"name":"Department of Microbiology, Tumor and Cell Biology Karolinska Institute  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei\u2010Yun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of 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