{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:32:56Z","timestamp":1792427576953,"version":"4.5.0"},"reference-count":51,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T00:00:00Z","timestamp":1742256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&amp;D Program of China","doi-asserted-by":"publisher","award":["2023YFC3504000"],"award-info":[{"award-number":["2023YFC3504000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&amp;D Program of China","doi-asserted-by":"publisher","award":["81473360"],"award-info":[{"award-number":["81473360"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2023YFC3504000"],"award-info":[{"award-number":["2023YFC3504000"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81473360"],"award-info":[{"award-number":["81473360"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Chronic migraine (CM) is a common complex nervous system disease, often accompanied by symptoms of the digestive tract that interact with each other, leading to prolonged and difficult-to-cure migraines. These symptoms are associated with abnormalities in 5-HT and its receptors. Wuzhuyu decoction (WZYD) is a traditional Chinese medicine prescription commonly used in clinics to treat CM; it relieves gastrointestinal symptoms, such as nausea and vomiting; however, its mechanism is still unclear. Investigating the differences in the role of WZYD compared to existing drugs targeting 5-HT receptors in the treatment of CM not only helps elucidate its pathogenesis but also provides possibilities for the development of new therapeutic approaches. Methods: An inflammation soup (IS)-induced CM male rat model was established. Based on a preliminary experiment, the target of WZYD in treating CM was determined by network pharmacology, and verified by molecular docking. ELISA, immunofluorescence, western blot, and real-time quantitative polymerase chain reaction (RT-qPCR) were used to evaluate the expression levels of CM-related indicators (5-HT, calcitonin gene-related peptide (CGRP), and c-Fos) to ensure the successful establishment of the CM model and the effectiveness of the drug. On this basis, the protein expression levels of 5-HT1A\/3A receptors and their cAMP-response element binding protein (CREB) signaling pathway were detected by western blot and immunohistochemistry. The role of 5-HT1A\/3A receptors in the treatment of CM by WZYD was validated using a 5-HT1A receptor antagonist (WAY 100635) and a 5-HT3A receptor agonist (SR 57227). Results: The results showed that WZYD increased the expression of 5-HT in the brain, decreased the expression of CGRP, c-Fos, ionized calcium-binding adapter molecule 1 (Iba1), and relieved CM. At the same time, WZYD also increased the expression of the 5-HT1A receptor and decreased the expression of the 5-HT3A receptor in the brain and colon of CM rats. Subsequently, WZYD further exerted its brain-gut integrated therapeutic effects by regulating the CREB signaling pathway mediated by 5-HT1A\/3A receptors in the brain and colon of CM rats. Conclusions: WZYD not only regulates neurotransmitters in the brain and colon at the same time, but also specifically regulates 5-HT1A\/3A receptors in the brain and colon, which explains the characteristics and advantages of WZYD from a new perspective. While effectively relieving headache symptoms, it also improves related gastrointestinal symptoms, which is more conducive to the treatment of CM.<\/jats:p>","DOI":"10.3390\/ph18030426","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T06:02:40Z","timestamp":1742277760000},"page":"426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Wuzhuyu Decoction Relieves Chronic Migraine by Regulating 5-HT1A and 3A Receptors-Mediated CREB Signaling Pathway in Brain and Intestine"],"prefix":"10.3390","volume":"18","author":[{"given":"Zhimin","family":"Song","sequence":"first","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"},{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijing","family":"Li","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"},{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwei","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"},{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomeng","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"},{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"},{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zekuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"},{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keshu","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"},{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8892-7120","authenticated-orcid":false,"given":"Qixiang","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"},{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Gou","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"},{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"},{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muxin","family":"Gong","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China"},{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,18]]},"reference":[{"key":"ref_1","first-page":"527","article-title":"Rethinking clinical status of migraine","volume":"44","author":"Song","year":"2023","journal-title":"World Clin. 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