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Notably, calcitonin gene-related peptide (CGRP) has been identified as a key player in a signalling cascade involved in migraine attacks, acting through the second messenger cyclic adenosine monophosphate (cAMP) in various cells, including intracranial vascular smooth muscle cells. However, it remains unclear whether intracellular cAMP signalling requires CGRP receptor activation during a migraine attack in humans. To address this question, we conducted a randomized, double-blind, placebo-controlled, parallel trial using a human provocation model involving the administration of CGRP and cilostazol in individuals with migraine pretreated with erenumab or placebo. Our study revealed that migraine attacks can be provoked in patients by cAMP-mediated mechanisms using cilostazol, even when the CGRP receptor is blocked by erenumab. Furthermore, the dilation of cranial arteries induced by cilostazol was not influenced by the CGRP receptor blockade. These findings provide clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. This discovery opens up new possibilities for the development of mechanism-based drugs for the treatment of migraine.<\/jats:p>","DOI":"10.1093\/brain\/awad261","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T13:07:31Z","timestamp":1691154451000},"page":"5224-5234","source":"Crossref","is-referenced-by-count":33,"title":["Second messenger signalling bypasses CGRP receptor blockade to provoke migraine attacks in humans"],"prefix":"10.1093","volume":"146","author":[{"given":"Thien Phu","family":"Do","sequence":"first","affiliation":[{"name":"Department of Neurology, Danish Headache Center, Copenhagen University Hospital\u2014Rigshospitalet , Copenhagen , Denmark"},{"name":"Department of Clinical Medicine, University of Copenhagen , Copenhagen , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Deligianni","sequence":"additional","affiliation":[{"name":"Department of Neurology, Danish Headache Center, Copenhagen University Hospital\u2014Rigshospitalet , Copenhagen , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarkhan","family":"Amirguliyev","sequence":"additional","affiliation":[{"name":"Department of Neurology, Danish Headache Center, Copenhagen University Hospital\u2014Rigshospitalet , Copenhagen , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefin","family":"Snellman","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG , 4056 Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina Lopez","family":"Lopez","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Basel, F. 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