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In the present study, we identified hyperalgesia sexual dimorphism involving LPA1\/3 signaling in the intermittent psychological stress induced-related FM-like model called intermittent psychological stress (IPS)-induced generalized pain (IPGP) model where the hyperalgesia in IPGP mice was abolished in LPA1- and LPA3-knock-out mice. Pharmacological intervention by intraperitoneal (i.p.) treatments with the LPA1\/3 antagonist Ki16425 consistently prevented hyperalgesia. However, intracerebroventricular treatments with Ki16425 abolished hyperalgesia in male, but not female, mice. Notably, intrathecal treatments of Ki16425 did not prevent hyperalgesia. Further studies revealed that splenocytes derived from female IPGP mice could initiate hyperalgesia via adoptive transfer in na\u00efve mice, and this effect was abolished when donor mice were pre-treated with Ki16425 (i.p.). Thus, these studies identify male-specific LPA1\/3-mediated mechanisms in the brain underlying IPGP, as well as distinct LPA-LPA1\/3-mediated peripheral immune mechanisms.<\/jats:p>","DOI":"10.3390\/cells14131022","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T11:20:11Z","timestamp":1751628011000},"page":"1022","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hyperalgesia in the Psychological Stress-Induced Fibromyalgia Model Shows Sexual Dimorphism Mediated by LPA1 and LPA3"],"prefix":"10.3390","volume":"14","author":[{"given":"Hiroshi","family":"Ueda","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutic Innovation, Nagasaki University Institute of Biomedical Sciences, Nagasaki 852-8521, Japan"},{"name":"Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan"},{"name":"Laboratory for the Study of Pain, Research Institute for Production Development, Kyoto 606-0805, Japan"},{"name":"Graduate Institute of Pharmacology, National Defense Medical Center, Nei-hu, Taipei 114201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3351-9813","authenticated-orcid":false,"given":"Hiroyuki","family":"Neyama","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutic Innovation, Nagasaki University Institute of Biomedical Sciences, Nagasaki 852-8521, Japan"},{"name":"Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Dozono","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutic Innovation, Nagasaki University Institute of Biomedical Sciences, Nagasaki 852-8521, Japan"},{"name":"Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junken","family":"Aoki","sequence":"additional","affiliation":[{"name":"Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3964-0921","authenticated-orcid":false,"given":"Jerold","family":"Chun","sequence":"additional","affiliation":[{"name":"Center for Neurological Diseases, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.jpain.2008.12.001","article-title":"Sex, gender, and pain: A review of recent clinical and experimental findings","volume":"10","author":"Fillingim","year":"2009","journal-title":"J. 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