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This study aimed to investigate the role of astrocyte activation and evaluate the therapeutic potential of targeted astrocyte inhibition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic triptan use for migraine can lead to MOH, characterized by persistent hyperalgesia and high relapse rates. The mechanisms underlying this transition remain poorly understood. Although central sensitization and neuroinflammation are implicated, the specific contribution of astrocytes in TNC has not been investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A rat MOH model was established by repeated intraperitoneal administration of sumatriptan for 9\u2009days. Cutaneous allodynia was assessed using von Frey filaments, and latent sensitization was evaluated under the 0.5\u2009mg\/kg nitroglycerin challenge. To selectively inhibit astrocyte activation, an adeno\u2010associated virus vector was injected into bilateral TNC, followed by the administration of its ligand, deschloroclozapine. Neuronal (cellular proto\u2010oncogene Fos, calcitonin gene\u2010related peptide, postsynaptic density protein 95, and synaptophysin), microglial (ionized calcium\u2010binding adapter molecule 1), and astrocytic (glial fibrillary acidic protein) markers, along with proinflammatory mediators (inducible nitric oxide synthase, tumor necrosis factor\u2010alpha, etc.), were analyzed via immunofluorescence and Western blot.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Repeated sumatriptan induced long\u2010term cutaneous allodynia and latent sensitization. This process was accompanied by transient activation of neurons and microglia, and a short\u2010term increase in synaptic proteins and proinflammatory cytokines in TNC. However, astrocyte activation sustained after the behavioral hypersensitivity had apparently resolved. Chemogenetic inhibition of astrocytes in TNC prevented the development of long\u2010term cutaneous allodynia and latent sensitization. This intervention also ameliorated the overexpression of synaptic proteins and proinflammatory cytokines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings demonstrate that sustained astrocyte activation in TNC is a potential driver of prolonged hyperalgesia in triptan\u2010induced MOH. Inhibiting astrocyte activity effectively reverses behavioral and molecular markers of MOH, highlighting astrocyte inhibition as a promising therapeutic strategy for MOH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/head.70127","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T03:28:01Z","timestamp":1780975681000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibiting astrocyte activation is effective in triptan\u2010induced medication\u2010overuse headache model and prolonged hyperalgesia"],"prefix":"10.1111","author":[{"given":"Yanyun","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Chongqing Medical University  Chongqing People's Republic of 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