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We also hypothesized this involves an increased sensitivity of the striatal striosomal neurons that co-express MORs and dopamine D\n                    <jats:sub>1<\/jats:sub>\n                    receptors (D\n                    <jats:sub>1<\/jats:sub>\n                    Rs) and release GABA in the internal segment of the globus pallidus (GPi). This hypothesis was tested in mice with diet-induced brain iron deficiency (BID), a rodent model of RLS. Fiber-photometry experiments were performed in mice with BID using a viral GABA biosensor injected in the entopeduncular nucleus (EPN), the GPi equivalent in rodents. EPN GABA release was measured after the systemic administration of the D\n                    <jats:sub>1<\/jats:sub>\n                    R agonist SKF81297 and the MOR agonist methadone. Locomotor activation and striatal mRNA expression of D\n                    <jats:sub>1<\/jats:sub>\n                    Rs, MORs and adenosine A\n                    <jats:sub>1<\/jats:sub>\n                    receptors (A\n                    <jats:sub>1<\/jats:sub>\n                    Rs) were also analyzed. A minimal locomotor-activating dose of SKF81297 induced a significant EPN GABA release in mice with BID but not controls, while a maximal locomotor-activating dose of the MOR agonist methadone significantly reduced EPN GABA release in mice with BID after saline or SKF81297 administration. BID was associated with a significant reduction in the striatal expression of MORs and A\n                    <jats:sub>1<\/jats:sub>\n                    Rs. The results indicate that BID induces an increased dopaminergic sensitivity of the opioid-responsive striatal\u2013EPN pathway, which might represent a pivotal pathogenetic mechanism of the restlessness of RLS and opioid withdrawal.\n                  <\/jats:p>","DOI":"10.1038\/s41386-026-02413-2","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T16:13:22Z","timestamp":1776442402000},"page":"1865-1872","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dopaminergic hypersensitivity of the opioid-responsive striatal\u2013entopeduncular pathway in a rodent model of restless legs syndrome"],"prefix":"10.1038","volume":"51","author":[{"given":"Marta","family":"Valle-Le\u00f3n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Rea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9sar","family":"Quiroz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7723-0064","authenticated-orcid":false,"given":"William N.","family":"S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Albornoz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana M.","family":"Rule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning-Sheng","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0832-3739","authenticated-orcid":false,"given":"Francisco","family":"Ciruela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Earley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1747-1779","authenticated-orcid":false,"given":"Sergi","family":"Ferr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"2413_CR1","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.1056\/NEJMcp021288","volume":"348","author":"CJ Earley","year":"2003","unstructured":"Earley CJ. 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