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Modafinil, a wake-promoting drug, manages pain symptoms in several diseases by inhibiting dopamine reuptake and exhibiting anti-inflammatory and immunomodulatory effects, including the impairment of cytokine production, microglia, and mast cell activation. Central inflammation may involve microglial activation, which is correlated with mast cell activation. Restoring dopamine levels and modulating the communication between mast cells and microglia may represent a promising approach to managing pain symptoms in FMS. Thus, this study intended to explore the interplay between brain mast cells and microglia as an underlying mechanism in the pathophysiology of FMS and how this interaction is controlled by modafinil, with a focus on dopamine\/SP\/MRGPRX2\/histamine and PI3K\/p-Akt\/NF-\u03baB signaling pathways. Rats were arbitrarily distributed between 4 groups. Group 1 served as normal control. Reserpine (1\u00a0mg\/kg\/day; s.c) was injected into the remaining groups for three consecutive days. In groups 3 and 4, modafinil (100\u00a0mg\/kg\/day; p.o) was administered either alone or in conjunction with haloperidol (1\u00a0mg\/kg\/day; ip), respectively, for the following 21\u00a0days. Modafinil ameliorated reserpine-induced thermal\/mechanical allodynia (1.3-fold, 2.3-fold) and hyperalgesia (0.5-fold), attenuated depression (0.5-fold), and enhanced motor coordination (1.2-fold). It mitigated the histopathological alterations and increased dopamine levels in the thalamus of rats by 88.5%. Modafinil displayed anti-inflammatory effects via inhibiting mast cells and microglia activation, manifested by reductions in SP\/MRGPRX2\/IL-17\/histamine (52%, 58%, 56.7%, and 63.7%) and PI3K\/p-Akt\/t-Akt\/NF-\u03baB\/TNF-\u03b1\/IL-6 (31.7%, 55.5%, 41%, 47.6%, and 76.9%), respectively. Ultimately, modafinil alleviated FMS behavioral, histopathological, and biochemical abnormalities and suppressed mast cell-microglial neuroinflammation in the thalamus of rats exposed to reserpine. This study highlights the potential of repurposing modafinil to improve FMS symptoms.<\/jats:p>","DOI":"10.1007\/s11481-025-10194-6","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T13:02:26Z","timestamp":1744722146000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Modafinil Ameliorated Fibromyalgia Syndrome in Rats by Modulating Mast Cells and Microglia Activation Through Dopamine\/Substance P\/MRGPRX\/Histamine and PI3K\/p-Akt\/NF-\u03baB Signaling Pathways"],"prefix":"10.1007","volume":"20","author":[{"given":"Mennat-Allah M.","family":"Kamal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reham M.","family":"Essam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7026-283X","authenticated-orcid":false,"given":"Noha F.","family":"Abdelkader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala F.","family":"Zaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"10194_CR1","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1007\/s12272-022-01391-5","volume":"45","author":"NF Abdelkader","year":"2022","unstructured":"Abdelkader NF, Elbaset MA, Moustafa PE, Ibrahim SM (2022) Empagliflozin mitigates type 2 diabetes-associated peripheral neuropathy: a glucose-independent effect through AMPK signaling. 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