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We now report the first finding of CGRP-induced nociceptive neuronal activation using a novel method of intra-carotid infusion to achieve a more targeted delivery to cranial tissues.<\/jats:p>\n                  <jats:p>Single-unit recordings were performed in anaesthetized rats to measure CGRP effects on first- and second-order trigeminovascular neurons. CGRP was administered via intra-carotid infusion. Neuronal activation and sensitization were assessed by spontaneous firing rates and responses to mechanical stimulation of dural and facial receptive fields. Lidocaine was applied locally to the dura or trigeminal ganglion at varying time points to determine the peripheral contribution to CGRP-induced activity.<\/jats:p>\n                  <jats:p>Intra-carotid CGRP infusion (5\u2005\u00b5g\/kg\/min, 20\u2005min) activated 62% of A\u03b4-fibres and 56% of C-fibres, with significant increases in firing rates beginning within the first 30\u2005min for A\u03b4-fibres and after 1\u2005h for C-fibres. It also activated 75% of central trigeminovascular neurons, significantly increasing spontaneous firing and sensitizing dural and facial receptive fields. Similar effects were produced by CGRP injection into the trigeminal ganglion. These effects of CGRP were impeded by local anaesthetic blockade of the dura or trigeminal ganglion before but not 1\u2005h after CGRP infusion. No significant sex differences were found in baseline firing or in the magnitude and timing of CGRP-induced responses across all neuron types.<\/jats:p>\n                  <jats:p>These findings provide the first evidence of peripheral nociceptive neuronal activation by CGRP, with a site of action in the meninges, and support a rationale for early, peripherally acting CGRP-targeted migraine treatments.<\/jats:p>","DOI":"10.1093\/brain\/awag008","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T12:46:55Z","timestamp":1767790015000},"page":"2760-2773","source":"Crossref","is-referenced-by-count":6,"title":["Elucidating the nociceptive role of CGRP in migraine headache"],"prefix":"10.1093","volume":"149","author":[{"given":"Agustin","family":"Melo-Carrillo","sequence":"first","affiliation":[{"name":"Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center , Boston, MA 02115 ,","place":["USA"]},{"name":"Department of Anesthesia, Harvard Medical School , Boston, MA 02115 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M","family":"Strassman","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center , Boston, MA 02115 ,","place":["USA"]},{"name":"Department of Anesthesia, Harvard Medical School , Boston, MA 02115 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3763-8916","authenticated-orcid":false,"given":"Rami","family":"Burstein","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center , Boston, MA 02115 ,","place":["USA"]},{"name":"Department of Anesthesia, Harvard Medical School , Boston, MA 02115 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