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Yet how CGRP induces delayed migraine-like pain after systemic infusion remains unresolved. Despite strong clinical and experimental evidence for its role, the mechanisms linking CGRP signaling to trigeminovascular nociception are still unclear. Based on a comprehensive review of the experimental literature, we propose a hypothesis, in which CGRP initiates a delayed signaling cascade that ultimately sensitizes trigeminal afferents. In this framework, CGRP promotes not only arterial vasodilatation but activates glial responses involving transcription-dependent processes and ion channel modulation that evolve over hours and provide a mechanistic explanation for the delayed onset of migraine-like pain. We further propose that peripheral endothelial\u2013glial signaling may be amplified at ganglionic and spinal levels, contributing to trigeminovascular sensitization. In spontaneous migraine attacks, CGRP release appears as a consequence of primary afferent excitation through an excess of nitric oxide species activating transient receptor potential channels, most likely initiated by an endothelial dysfunction through metabolic disturbances including cortical spreading depression. These peripheral mechanisms do not exclude central changes that govern the periodic susceptibility of migraine and cluster headache attacks. Our model integrates existing observations regarding CGRP biology, delayed migraine induction, and glial signaling into a unified framework. We reframe migraine generation as a neuro-glial process and highlight new targets for therapeutic intervention.<\/jats:p>","DOI":"10.1186\/s10194-026-02455-3","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T17:36:41Z","timestamp":1784223401000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A delayed endothelial\u2013glial mechanism for CGRP-induced migraine"],"prefix":"10.1186","volume":"27","author":[{"given":"Jochen K.","family":"Lennerz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8099-3860","authenticated-orcid":false,"given":"Karl","family":"Messlinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"2455_CR1","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1038\/298240a0","volume":"298","author":"SG Amara","year":"1982","unstructured":"Amara SG, Jonas V, Rosenfeld MG et al (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. 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