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Recently, we demonstrated that E2 significantly exacerbates adverse health effects, such as respiratory distress and weight loss, in ovariectomized (OVX) female rats during withdrawal from extended\u2010access fentanyl self\u2010administration. To uncover the mechanisms behind E2\u2010enhanced toxicity, we investigated proteomic changes in the plasma of fentanyl\u2010withdrawn OVX rats under both E2 and non\u2010E2 presentation conditions.Plasma samples were collected following extended\u2010access fentanyl self\u2010administration during protracted withdrawal, when adverse health effects were most pronounced. Using liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC\u2010ESI MS\/MS) we conducted proteomic analysis in OVX rats comparing the effect of fentanyl withdrawal, with or without E2, to drug\u2010na\u00efve control rats.We found a significant effect of fentanyl withdrawal on plasma proteomes within OVX rats. Fentanyl withdrawal was associated with a significant change in 15 plasma proteins including B\u2010factor, properdin (Cfb), apolipoprotein E (ApoE), complement 4, precursor (C4), C\u2010reactive protein (Crp), zinc\u2010alpha\u20102\u2010glycoprotein precursor (Azgp1), and serine peptidase inhibitor 3L (Serinpa3l). The addition of E2 was associated with enhanced proteomic changes. Bioinformatic gene ontology enrichment analysis indicates that fentanyl withdrawal can disrupt the expression of proteins associated with immunity, lipid transport, and components of the extracellular matrix. We identify protein changes in plasma that may contribute to adverse health outcomes in females, with and without E2, during fentanyl withdrawal. These findings support the development of targeted strategies addressing health risks during opioid use disorder in women.<\/jats:p>","DOI":"10.1111\/jne.70033","type":"journal-article","created":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T21:14:51Z","timestamp":1745183691000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Proteomic analysis of plasma proteins during fentanyl withdrawal in ovariectomized female rats with and without estradiol"],"prefix":"10.1111","volume":"37","author":[{"given":"Patricia","family":"Sinclair","sequence":"first","affiliation":[{"name":"Interdisciplinary Program in Neuroscience George Mason University  Fairfax Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navdeep S.","family":"Dhanjal","sequence":"additional","affiliation":[{"name":"Bioinformatics and Computational Biology Program George Mason University  Manassas Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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