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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,3,28]]},"abstract":"<jats:p>Sleep\/wake control involves several neurotransmitter and neuromodulatory systems yet the coordination of the behavioral and physiological processes underlying sleep is incompletely understood. Previous studies have suggested that activation of the Nociceptin\/orphanin FQ (N\/OFQ) receptor (NOPR) reduces locomotor activity and produces a sedation-like effect in rodents. In the present study, we systematically evaluated the efficacy of two NOPR agonists, Ro64-6198 and SR16835, on sleep\/wake in rats, mice, and Cynomolgus macaques. We found a profound, dose-related increase in non-Rapid Eye Movement (NREM) sleep and electroencephalogram (EEG) slow wave activity (SWA) and suppression of Rapid Eye Movement sleep (REM) sleep in all three species. At the highest dose tested in rats, the increase in NREM sleep and EEG SWA was accompanied by a prolonged inhibition of REM sleep, hypothermia, and reduced locomotor activity. However, even at the highest dose tested, rats were immediately arousable upon sensory stimulation, suggesting sleep rather than an anesthetic state. NOPR agonism also resulted in increased expression of c-Fos in the anterodorsal preoptic and parastrial nuclei, two GABAergic nuclei that are highly interconnected with brain regions involved in physiological regulation. These results suggest that the N\/OFQ\u2013NOPR system may have a previously unrecognized role in sleep\/wake control and potential promise as a therapeutic target for the treatment of insomnia.<\/jats:p>","DOI":"10.1073\/pnas.2214171120","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T13:22:41Z","timestamp":1679491361000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":19,"title":["Activation of the nociceptin\/orphanin-FQ receptor promotes NREM sleep and EEG slow wave activity"],"prefix":"10.1073","volume":"120","author":[{"given":"Stephen R.","family":"Morairty","sequence":"first","affiliation":[{"name":"Biosciences Division, Center for Neuroscience, SRI International, Menlo Park, CA 94025"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5002-1414","authenticated-orcid":false,"given":"Yu","family":"Sun","sequence":"additional","affiliation":[{"name":"Biosciences Division, Center for Neuroscience, SRI International, Menlo Park, CA 94025"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4501-7573","authenticated-orcid":false,"given":"Lawrence","family":"Toll","sequence":"additional","affiliation":[{"name":"Biosciences Division, Center for Neuroscience, SRI International, Menlo Park, CA 94025"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4713-7816","authenticated-orcid":false,"given":"Michael R.","family":"Bruchas","sequence":"additional","affiliation":[{"name":"Center for Neurobiology of Addiction, Pain, and Emotion, University of Washington, Seattle, WA 98195"},{"name":"Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98195"},{"name":"Department of Pharmacology, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6823-0094","authenticated-orcid":false,"given":"Thomas S.","family":"Kilduff","sequence":"additional","affiliation":[{"name":"Biosciences Division, Center for Neuroscience, SRI International, Menlo Park, CA 94025"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,3,22]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"239","article-title":"Effect of short sleep duration on daily activities\u2014United States, 2005 to 2008","volume":"60","author":"CDC","year":"2011","unstructured":"CDC, Effect of short sleep duration on daily activities\u2014United States, 2005 to 2008. 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