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The current study investigates atogepant effect on CSD-induced activation and sensitization of high threshold (HT) and wide dynamic range (WDR) central dura-sensitive trigeminovascular neurons.<\/jats:p>\n                  <jats:p>In anaesthetized male rats, single-unit recordings were used to assess effects of atogepant (5 mg\/kg) versus vehicle on CSD-induced activation and sensitization of HT and WDR trigeminovascular neurons.<\/jats:p>\n                  <jats:p>Single cell analysis of atogepant pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus revealed the ability of this small molecule CGRP receptor antagonist to prevent activation and sensitization of nearly all HT neurons (8\/10 versus 1\/10 activated neurons in the control versus treated groups, P = 0.005). In contrast, atogepant pretreatment effects on CSD-induced activation and sensitization of WDR neurons revealed an overall inability to prevent their activation (7\/10 versus 5\/10 activated neurons in the control versus treated groups, P = 0.64). Unexpectedly however, in spite of atogepant\u2019s inability to prevent activation of WDR neurons, it prevented their sensitization (as reflected their responses to mechanical stimulation of the facial receptive field before and after the CSD).<\/jats:p>\n                  <jats:p>Atogepant\u2019 ability to prevent activation and sensitization of HT neurons is attributed to its preferential inhibitory effects on thinly myelinated A\u03b4 fibres. Atogepant\u2019s inability to prevent activation of WDR neurons is attributed to its lesser inhibitory effects on the unmyelinated C fibres. Molecular and physiological processes that govern neuronal activation versus sensitization can explain how reduction in CGRP-mediated slow but not glutamate-mediated fast synaptic transmission between central branches of meningeal nociceptors and nociceptive neurons in the spinal trigeminal nucleus can prevent their sensitization but not activation.<\/jats:p>","DOI":"10.1093\/brain\/awae062","type":"journal-article","created":{"date-parts":[[2024,2,24]],"date-time":"2024-02-24T01:02:27Z","timestamp":1708736547000},"page":"2884-2896","source":"Crossref","is-referenced-by-count":37,"title":["Novel insight into atogepant mechanisms of action in migraine prevention"],"prefix":"10.1093","volume":"147","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 , USA"},{"name":"Harvard Medical School , Harvard University, Boston, MA 02115 , 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 , USA"},{"name":"Harvard Medical School , Harvard University, Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron","family":"Broide","sequence":"additional","affiliation":[{"name":"Allergan, an Abbvie Company , Irvine, CA 92612 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aubrey","family":"Adams","sequence":"additional","affiliation":[{"name":"Allergan, an Abbvie Company , Irvine, CA 92612 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Dabruzzo","sequence":"additional","affiliation":[{"name":"Allergan, an Abbvie Company , Irvine, CA 92612 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell","family":"Brin","sequence":"additional","affiliation":[{"name":"Allergan, an Abbvie Company , Irvine, CA 92612 , USA"},{"name":"Department of Neurology, University of California , Irvine, CA 92697 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 . 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