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Wnt\/\u03b2-catenin signaling has shown a crucial role against depression in several studies. The FDA-approved FM drug, milnacipran (Miln), has shown antinociceptive potential against FM. Yet, no study has investigated its antidepressant potential in FM. Vanillin (Van), a well-known phytochemical often employed as flavoring agent, has been previously reported for its antidepressant and antinociceptive effects in several animal models, but has not been tested so far in FM. This study explored the antidepressant effect of Van and Miln in FM through investigating Wnt\/\u03b2-catenin signaling. FM was induced in female Wistar rats by injecting reserpine (1\u00a0mg\/kg\/day s.c) for 3\u00a0days. Thereafter, animals received either Miln (30\u00a0mg\/kg\/day p.o) or Van (100\u00a0mg\/kg\/day p.o) for the subsequent 14\u00a0days. Results showed that both drugs demonstrated antidepressant effect in forced swimming test besides analgesic, and antiallodynic influences observed in Randall-Selitto, hot plate, cold allodynia, Von-Frey, and tail immersion tests. Biochemically, Miln and Van significantly enhanced serotonergic transmission in the hippocampus and upregulated the protein expression of the Wnt\/GSK-3\u03b2\/\u03b2-catenin signaling axis, including the downstream proteins, T cell factor, and dicer. This is followed by subsequent upregulation of the resilience micro ribonucleic acids (miRNAs) 124 and 135. Histopathological examinations corroborated the biochemical and molecular findings. Interestingly, these effects of Miln and Van were overturned via administration of the \u03b2-catenin inhibitor, XAV939 (0.1\u00a0mg\/kg, i.p., daily). In conclusion, this study outlined the antidepressant aptitude of Miln and Van through activating Wnt\/\u03b2-catenin signaling in the hippocampus in reserpine-induced FM.<\/jats:p>","DOI":"10.1007\/s12035-025-04723-w","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T03:53:19Z","timestamp":1739159599000},"page":"7682-7705","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Milnacipran and Vanillin Alleviate Fibromyalgia-Associated Depression in Reserpine-Induced Rat Model: Role of Wnt\/\u03b2-Catenin Signaling"],"prefix":"10.1007","volume":"62","author":[{"given":"Nour A.","family":"Kamaly","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed S.","family":"Kamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nermin Abdelhamid","family":"Sadik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9746-5335","authenticated-orcid":false,"given":"Nancy N.","family":"Shahin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"4723_CR1","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1007\/S40122-024-00641-2","volume":"13","author":"A Badaeva","year":"2024","unstructured":"Badaeva A, Danilov A, Kosareva A et al (2024) Neuronutritional approach to fibromyalgia management: a narrative review. 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