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PAE is a risk factor for developing peripheral immune and spinal glial sensitization and release of the proinflammatory cytokine IL\u20101\u03b2, which lead to neuropathic pain (allodynia) from minor nerve injury. Although morphine acts on \u03bc\u2010opioid receptors, it also activates immune receptors, TLR4, and the NLRP3 inflammasome that induces IL\u20101\u03b2. We hypothesized that PAE induces NLRP3 sensitization by morphine following nerve injury in adult mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used an established moderate PAE paradigm, in which adult PAE and non\u2010PAE control female mice were exposed to a minor sciatic nerve injury, and subsequent allodynia was measured using the von Frey fiber test. In control mice with standard sciatic damage or PAE mice with minor sciatic damage, the effects of the NLRP3 inhibitor, MCC950, were examined during chronic allodynia. Additionally, minor nerve\u2010injured mice were treated with morphine, with or without MCC950. In\u00a0vitro studies examined the TLR4\u2010NLRP3\u2010dependent proinflammatory response of peripheral macrophages to morphine and\/or lipopolysaccharide, with or without MCC950.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mice with standard sciatic damage or PAE mice with minor sciatic damage developed robust allodynia. Blocking NLRP3 activation fully reversed allodynia in both control and PAE mice. Morphine paradoxically prolonged allodynia in PAE mice, while control mice with minor nerve injury remained stably non\u2010allodynic. Allodynia resolved sooner in nerve\u2010injured PAE mice without morphine treatment than in morphine\u2010treated mice. MCC950 treatment significantly shortened allodynia in morphine\u2010treated PAE mice. Morphine potentiated IL\u20101\u03b2 release from TLR4\u2010activated PAE immune cells, while MCC950 treatment greatly reduced it.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In female mice, PAE prolongs allodynia following morphine treatment through NLRP3 activation. TLR4\u2010activated PAE immune cells showed enhanced IL\u20101\u03b2 release with morphine via NLRP3 actions. Similar studies are needed to examine the adverse impact of morphine in males with PAE. These results are predictive of adverse responses to opioid pain therapeutics in individuals with FASD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.15214","type":"journal-article","created":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T09:48:05Z","timestamp":1698313685000},"page":"2262-2277","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Prenatal alcohol exposure promotes NLRP3 inflammasome\u2010dependent immune actions following morphine treatment and paradoxically prolongs nerve injury\u2010induced pathological pain in female mice"],"prefix":"10.1111","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4446-8279","authenticated-orcid":false,"given":"Shahani","family":"Noor","sequence":"first","affiliation":[{"name":"Department of Neurosciences, School of Medicine University of New Mexico  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melody S.","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medicine University of New Mexico  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea A.","family":"Pasmay","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medicine University of New Mexico  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariana N.","family":"Pritha","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medicine University of New Mexico  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4841-9743","authenticated-orcid":false,"given":"Chaselyn D.","family":"Ruffaner\u2010Hanson","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medicine University of New Mexico  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique V.","family":"Nysus","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medicine University of New Mexico  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane C.","family":"Jimenez","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medicine University of New Mexico  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minerva","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medicine University of New Mexico  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1726-1103","authenticated-orcid":false,"given":"Daniel D.","family":"Savage","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medicine University of New Mexico  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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