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In this study, an excitatory projection from the cingulate cortex (Cg) to the intermediate rostrocaudal division of zona incerta (ZIm) is revealed that is activated by morphine in mice. Chemogenetic inhibition of the Cg\u2010ZIm pathway decreased high\u2010dose (10\u201315mg\u00a0kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) morphine\u2010induced hyperlocomotion without affecting its analgesic effects. Activation of this pathway faithfully reproduced the motor effect of morphine. Furthermore, high\u2010dose morphine\u2010induced hyperlocomotion is quickly attenuated by microinjecting delta\u2010opioid receptor (DOR) antagonists into the ZI, which is not observed following the targeted knockout of the DOR in Cg\u2010projecting ZI neurons, indicating a postsynaptic DOR\u2010mediated mechanism. In summary, these findings identify the critical role of the DOR within the Cg\u2010ZIm circuit in the psychomotor properties of morphine. This work sheds light on potential targets within the Cg\u2010ZIm pathway for mitigating the undesired psychomotor effects of morphine and thereby optimizing its clinical outcomes.\n                  <\/jats:p>","DOI":"10.1002\/advs.202503831","type":"journal-article","created":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T17:16:52Z","timestamp":1764523012000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Delta Opioid Receptors within the Cortico\u2010Thalamic Circuitry Underlie Hyperactivity Induced by High\u2010Dose Morphine"],"prefix":"10.1002","volume":"13","author":[{"given":"Chun\u2010Yue","family":"Li","sequence":"first","affiliation":[{"name":"Department of Psychiatry of the Second Affiliated Hospital and Liangzhu Laboratory Zhejiang University School of Medicine  Hangzhou 310058 China"},{"name":"Department of Anesthesiology of Second Affiliated Hospital Zhejiang University School of Medicine  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