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To identify the underlying neural circuits, we reverse-translated a conditioned placebo protocol from humans to mice. Surprisingly, the placebo effect suppresses both nociception and unconditioned emotional-motivational pain-related behavior. Descending pain modulatory neurons in the periaqueductal gray (PAG) are critical for both morphine and placebo antinociception. The placebo effect depends on input to the PAG from the medial prefrontal and anterior cingulate cortices, but not anterior insular cortex. Conditioning enhances noxious stimulus-evoked endogenous opioid release in the PAG to produce analgesia. Our results suggest that cortical control of the descending pain modulatory system (DPMS) is gated by rapid endogenous opioid signaling in the PAG during placebo trials. This study bridges clinical and preclinical research, establishing a central role for the DPMS in placebo analgesia.<\/jats:p>","DOI":"10.1101\/2025.02.13.638185","type":"posted-content","created":{"date-parts":[[2025,2,16]],"date-time":"2025-02-16T22:05:15Z","timestamp":1739743515000},"source":"Crossref","is-referenced-by-count":2,"title":["Top-down control of the descending pain modulatory system drives placebo analgesia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8787-7777","authenticated-orcid":false,"given":"Giulia","family":"Livrizzi","sequence":"first","affiliation":[{"name":"Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA"},{"name":"Biological Sciences Graduate Program, University of California San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9269-6396","authenticated-orcid":false,"given":"Jingzhu","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4749-5982","authenticated-orcid":false,"given":"Desiree A.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7553-9586","authenticated-orcid":false,"given":"Susan T.","family":"Lubejko","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA"},{"name":"Neurosciences Graduate Program, University of California San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9757-7501","authenticated-orcid":false,"given":"Janie","family":"Chang-Weinberg","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA"},{"name":"Biological Sciences Graduate Program, University of California San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4820-4454","authenticated-orcid":false,"given":"Chunyang","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7012-6926","authenticated-orcid":false,"given":"Lin","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, CA, USA"},{"name":"Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7248-2932","authenticated-orcid":false,"given":"Matthew R.","family":"Banghart","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041110063879000_2025.02.13.638185v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3976"},{"key":"2026041110063879000_2025.02.13.638185v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.10.023"},{"key":"2026041110063879000_2025.02.13.638185v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.02.042"},{"key":"2026041110063879000_2025.02.13.638185v1.4","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-01-00484.1999"},{"key":"2026041110063879000_2025.02.13.638185v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3923"},{"key":"2026041110063879000_2025.02.13.638185v1.6","first-page":"2616","article-title":"Increasing placebo responses over time in U","volume":"156","year":"2015","journal-title":"S. clinical trials of neuropathic pain. 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