{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T20:54:47Z","timestamp":1780520087563,"version":"3.54.1"},"reference-count":82,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T00:00:00Z","timestamp":1669075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health","award":["GR-2011-02346912"],"award-info":[{"award-number":["GR-2011-02346912"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>As a widely prescribed anti-diabetic drug, metformin has been receiving novel attention for its analgesic potential. In the study of the complex etiology of neuropathic pain (NeP), male and female individuals exhibit quite different responses characterized by higher pain sensitivity and greater NeP incidence in women. This \u201cgender gap\u201d in our knowledge of sex differences in pain processing strongly limits the sex-oriented treatment of patients suffering from NeP. Besides, the current investigation of the analgesic potential of metformin has not addressed the \u201cgender gap\u201d problem. Hence, this study focuses on metformin and sex-dependent analgesia in a murine model of NeP induced by chronic constriction injury of the sciatic nerve. We investigated sexual dimorphism in signaling pathways involved by 7 days of metformin administration, such as changes in AMP-activated protein kinase and the positive regulation of autophagy machinery, discovering that metformin affected in a sexually dimorphic manner the immunological and inflammatory response to nerve lesion. These effects were complemented by morphological and adaptive changes occurring after peripheral nerve injury. Altogether these data can contribute to explaining a number of potential mechanisms responsible for the complete recovery from NeP found in male mice, as opposed to the failure of long-lasting recovery in female animals.<\/jats:p>","DOI":"10.3390\/ijms232314503","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T08:25:28Z","timestamp":1669105528000},"page":"14503","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Sex Differences in Neuropathy: The Paradigmatic Case of MetFormin"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5773-3414","authenticated-orcid":false,"given":"Federica","family":"De Angelis","sequence":"first","affiliation":[{"name":"National Research Council (CNR), Institute of Biochemistry and Cell Biology, 00015 Monterotondo, RM, Italy"},{"name":"European Center for Brain Research\u2014IRCCS Santa Lucia Foundation, 00143 Rome, RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Vacca","sequence":"additional","affiliation":[{"name":"National Research Council (CNR), Institute of Biochemistry and Cell Biology, 00015 Monterotondo, RM, Italy"},{"name":"European Center for Brain Research\u2014IRCCS Santa Lucia Foundation, 00143 Rome, RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Tofanicchio","sequence":"additional","affiliation":[{"name":"Neurobiology, Department of Biology and Biotechnology \u201cCharles Darwin\u201d, Sapienza University of Rome, 00185 Rome, RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Strimpakos","sequence":"additional","affiliation":[{"name":"National Research Council (CNR), Institute of Biochemistry and Cell Biology, 00015 Monterotondo, RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Giacovazzo","sequence":"additional","affiliation":[{"name":"European Center for Brain Research\u2014IRCCS Santa Lucia Foundation, 00143 Rome, RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5189-2748","authenticated-orcid":false,"given":"Flaminia","family":"Pavone","sequence":"additional","affiliation":[{"name":"National Research Council (CNR), Institute of Biochemistry and Cell Biology, 00015 Monterotondo, RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7059-7015","authenticated-orcid":false,"given":"Roberto","family":"Coccurello","sequence":"additional","affiliation":[{"name":"European Center for Brain Research\u2014IRCCS Santa Lucia Foundation, 00143 Rome, RM, Italy"},{"name":"National Research Council (CNR), Institute for Complex System (ISC), 00185 Rome, RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5393-4796","authenticated-orcid":false,"given":"Sara","family":"Marinelli","sequence":"additional","affiliation":[{"name":"National Research Council (CNR), Institute of Biochemistry and Cell Biology, 00015 Monterotondo, RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"851","DOI":"10.2174\/1573399816666200206112318","article-title":"Reducing the Burden of Diabetes Treatment: A Review of Low-cost Oral Hypoglycemic Medications","volume":"16","author":"Vaughan","year":"2020","journal-title":"Curr. 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