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Semaglutide, an innovative glucagon-like peptide-1 (GLP-1) agonist, has shown analgesic effects by modulating pain hypersensitivity in animal models of inflammatory pain. The objective of this study is to ascertain semaglutide's therapeutic potential against FM-like symptoms caused by reserpine. Reserpine (1\u00a0mg\/kg\/day; SC) was administered into rats for 3 consecutive days, then they were treated daily with semaglutide intraperitoneally in low (5\u00a0nmol\/kg), intermediate (10\u00a0nmol\/kg), or high doses (20\u00a0nmol\/kg), respectively, for 14 consecutive days. Semaglutide alleviated reserpine induced histopathological and immunohistopathological changes in spinal cord of rats evidenced by a remarkable rise in immuno-expression of cluster of differentiation 163 (CD163) contrary to a significant diminution in CD86 level as compared with reserpine group. Semaglutide also had an analgesic effect and improved motor incoordination, and depression brought on by reserpine. Furthermore, it had an anti-inflammatory impact via stimulating cyclic adenosine monophosphate (cAMP)\/ protein kinase A (PKA)\/ cAMP response element (CRE)-binding protein (CREB) signaling pathway and shifting M1\/M2 macrophage polarization towards the M2. Semaglutide's anti-inflammatory actions were manifested through inhibition of inducible nitric oxide synthase and reduction in dorsal root ganglia concentrations of tumor necrosis factor-\u03b1 together with elevation in the levels of arginase-1 and interleukin-4.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1007\/s11481-025-10196-4","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T23:05:56Z","timestamp":1744844756000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Novel Trajectories Towards Possible Effects of Semaglutide for Amelioration of Reserpine-induced Fibromyalgia in Rats: Contribution of cAMP\/PKA\/p-CREB and M1\/M2 Microglia Polarization"],"prefix":"10.1007","volume":"20","author":[{"given":"Mena Z.","family":"Shafiek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala F.","family":"Zaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed F.","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weam W.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"issue":"11","key":"10196_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S13578-021-00554-Z","volume":"111","author":"N An","year":"2021","unstructured":"An N, Yang J, Wang H et al (2021) Mechanism of mesenchymal stem cells in spinal cord injury repair through macrophage polarization. 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