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Human RLS has been associated with abnormalities in the endogenous opioid system, the dopaminergic system, the iron regulatory system, anemia, and inflammatory and auto\u2010immune disorders. Our previous work indicates that mice lacking all three subtypes of opioid receptors have a phenotype similar to that of human RLS. To study the roles of each opioid receptor subtype in RLS, we first used mu opioid receptor knockout (MOR KO) mice based on our earlier studies using postmortem brain and cell culture. The KO mice showed decreased hemoglobin, hematocrit, and red blood cells (RBCs), with an appearance of microcytic RBCs indicating anemia. Together with decreased serum iron and transferrin, but increased ferritin levels, the anemia is similar to that seen with chronic inflammation in humans. A decreased serum iron level was also observed in the wildtype mice treated with an MOR antagonist. Iron was increased in the liver and spleen of the KO mice. Normal circadian variations in the dopaminergic and serotoninergic systems were absent in the KO mice. The KO mice showed hyperactivity and increased thermal sensitivity in wakefulness primarily during what would normally be the sleep phase similar to that seen in human RLS. Deficits in endogenous opioid system transmission could predispose to anemia of inflammation and loss of circadian variations in dopaminergic or serotonergic systems, thereby contributing to an RLS\u2010like phenotype.<\/jats:p>","DOI":"10.1002\/jnr.24637","type":"journal-article","created":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T04:08:25Z","timestamp":1589861305000},"page":"1532-1548","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mu opioid receptor knockout mouse: Phenotypes with implications on restless legs syndrome"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6566-6191","authenticated-orcid":false,"given":"Shangru","family":"Lyu","sequence":"first","affiliation":[{"name":"Norman Fixel Institute for Neurological Diseases, Department of Neurology, College of Medicine University of Florida Gainesville FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark P.","family":"DeAndrade","sequence":"additional","affiliation":[{"name":"Norman Fixel Institute for Neurological Diseases, Department of Neurology, College of Medicine University of Florida Gainesville FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erica L.","family":"Unger","sequence":"additional","affiliation":[{"name":"Department of Biology Lebanon Valley College Annville PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Mueller","sequence":"additional","affiliation":[{"name":"Mundipharma Research GmbH &amp; Co. 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