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It represents a major therapeutic challenge due to its pronounced sex differences in symptom manifestation and increased treatment resistance. Nitrous oxide (N\u2082O), an inhalational anesthetic traditionally used for its analgesic properties, has recently emerged as a potential rapid-acting antidepressant, with evidence suggesting both rapid and sustained antidepressant effects. Here, we evaluated the behavioral and electrophysiological effects of N\u2082O (50%, 1\u00a0h) in adult male and female mice subjected to the chronic constriction injury (CCI) model of neuropathic pain, assessing its potential to simultaneously target nociceptive and affective symptoms, as well as locomotor behavior. N\u2082O reduced locomotor activity in both sexes, with longer-lasting effects in males. EEG recordings revealed decreased low-frequency spectral power in both sham and CCI animals, with more widespread effects in females. In the acetone test, N\u2082O produced analgesia in CCI males but no significant effect in females, while stimulus application increased oscillatory EEG activity across groups and sexes. Notably, CCI females showed an attenuated electrophysiological response compared with Sham-Air controls. In sham animals, N\u2082O reduced post-stimulus power, whereas in CCI mice it restored prefrontal EEG activity, enhancing the electrophysiological responses in both sexes. In the tail suspension test, only CCI males exhibited a prodepressive phenotype, while no antidepressant-like effects were observed in either sex 24\u00a0h post-treatment. These findings demonstrate sex-specific behavioral and neurophysiological responses to N\u2082O, highlighting the importance of incorporating sex as a biological variable in NMDA receptor\u2013targeted interventions.<\/jats:p>","DOI":"10.1186\/s13293-026-00945-2","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T05:13:44Z","timestamp":1783401224000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex-specific electrophysiological and behavioral responses to nitrous oxide in a murine model of neuropathic pain"],"prefix":"10.1186","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3166-6537","authenticated-orcid":false,"given":"Gemma","family":"Gonz\u00e1lez-Hern\u00e1ndez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0255-6558","authenticated-orcid":false,"given":"Sonia","family":"Torres-Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5603-0936","authenticated-orcid":false,"given":"Daniel","family":"Sanchez-Morillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0052-1434","authenticated-orcid":false,"given":"Tomi","family":"Rantam\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0208-7472","authenticated-orcid":false,"given":"Esther","family":"Berrocoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"issue":"Suppl 1","key":"945_CR1","doi-asserted-by":"publisher","first-page":"S43","DOI":"10.1097\/j.pain.0000000000001311","volume":"159","author":"FM Blyth","year":"2018","unstructured":"Blyth FM, Huckel Schneider C. Global burden of pain and global pain policy-creating a purposeful body of evidence. Pain. 2018;159(Suppl 1):S43\u20138. https:\/\/doi.org\/10.1097\/j.pain.0000000000001311.","journal-title":"Pain"},{"key":"945_CR2","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1097\/j.pain.0000000000000454","volume":"157","author":"ASC Rice","year":"2016","unstructured":"Rice ASC, Smith BH, Blyth FM. Pain and the global burden of disease. Pain. 2016;157:791\u20136. https:\/\/doi.org\/10.1097\/j.pain.0000000000000454.","journal-title":"Pain"},{"key":"945_CR3","doi-asserted-by":"publisher","first-page":"2082","DOI":"10.1016\/S0140-6736(21)00393-7","volume":"397","author":"SP Cohen","year":"2021","unstructured":"Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances. Lancet Lond Engl. 2021;397:2082\u201397. https:\/\/doi.org\/10.1016\/S0140-6736(21)00393-7.","journal-title":"Lancet Lond Engl"},{"key":"945_CR4","doi-asserted-by":"publisher","first-page":"2433","DOI":"10.1001\/archinte.163.20.2433","volume":"163","author":"MJ Bair","year":"2003","unstructured":"Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003;163:2433\u201345. https:\/\/doi.org\/10.1001\/archinte.163.20.2433.","journal-title":"Arch Intern Med"},{"key":"945_CR5","doi-asserted-by":"publisher","first-page":"504691","DOI":"10.1155\/2015\/504691","volume":"2015","author":"L Doan","year":"2015","unstructured":"Doan L, Manders T, Wang J. Neuroplasticity underlying the comorbidity of pain and depression. 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