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(Hsp90) in pain and analgesia has been recognized; however, no study to date has investigated its role in facial allodynia during headache. In the current study, we examined the role of Hsp90 and its possible connection to the endocannabinoid system utilizing a rodent model of cortical spreading depression (CSD). Methods: CSD, a physiological phenomenon associated with headache disorders, was induced by cortical injection of KCl in female Sprague Dawley rats. To selectively inhibit Hsp90, 17-AAG was applied on the dura mater 24 h before CSD induction. Periorbital allodynia was assessed by von Frey filaments, while tissue samples were subjected to LC-MS, qPCR, Western immunoblotting, and the GTP\u03b3S coupling assay. Results: Increased expression of Hsp90 was selectively observed in the periaqueductal gray (PAG) harvested 90 min after cortical KCl injection, suggesting increased cellular stress from CSD induction. Application of 17-AAG (0.5 nmol) on dura mater 24 h before CSD induction significantly prevented facial allodynia as measured by von Frey filaments. This effect was blocked by injection of the CB1R antagonist rimonabant (1 mg\/kg, ip). The pretreatment with 17-AAG significantly increased the level of anandamide (AEA) in PAG 90 min after cortical insult, as measured by LC-MS. This effect was accompanied by reduced expression of FAAH and increased expression of NAPE-PLD in the same nuclei. Conclusions: These results suggest that Hsp90 inhibition positively modulates the endocannabinoid system, causing pain relief through descending pain modulation in PAG post-CSD.<\/jats:p>","DOI":"10.3390\/ph18101430","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T09:43:12Z","timestamp":1758706992000},"page":"1430","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Brain Hsp90 Inhibition Mitigates Facial Allodynia in a Rat Model of CSD Headache and Upregulates Endocannabinoid Signaling in the PAG"],"prefix":"10.3390","volume":"18","author":[{"given":"Seph M.","family":"Palomino","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Arizona, 1501 N. Campbell Avenue Tucson, Tucson, AZ 85719, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan A.","family":"Levine","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Arizona, 1501 N. Campbell Avenue Tucson, Tucson, AZ 85719, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Liktor-Busa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Arizona, 1501 N. Campbell Avenue Tucson, Tucson, AZ 85719, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2566-9312","authenticated-orcid":false,"given":"Parthasaradhireddy","family":"Tanguturi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Arizona, 1501 N. 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