{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T12:53:30Z","timestamp":1777726410104,"version":"3.51.4"},"reference-count":0,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005924","name":"International Association for the Study of Pain","doi-asserted-by":"publisher","award":["Early Career Research Grant"],"award-info":[{"award-number":["Early Career Research Grant"]}],"id":[{"id":"10.13039\/100005924","id-type":"DOI","asserted-by":"publisher"}]},{"award":["Early Career Research Grant"],"award-info":[{"award-number":["Early Career Research Grant"]}],"id":[{"id":"https:\/\/ror.org\/05dx8t190","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004895","name":"European Social Fund","doi-asserted-by":"publisher","award":["ESF (NORTE-08-5369-FSE-000026), Porto, Portugal"],"award-info":[{"award-number":["ESF (NORTE-08-5369-FSE-000026), Porto, Portugal"]}],"id":[{"id":"10.13039\/501100004895","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["NORTE-01-0145-FEDER-000008"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000008"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Opioids paradoxically induce hypersensitivity that typically resolves after discontinuation. Despite normalization of sensitivity, the nociceptive system may remain primed. Descending pathways contribute to opioid-induced hyperalgesia (OIH), and the following latently maintained sensitization. The mechanisms underlying the latter vulnerability remain unknown. We previously showed that the dorsal reticular nucleus (DRt), a key brainstem area involved in pain facilitation, drives OIH through a maladaptation in \u03bc-opioid receptor (MOR) signaling. Whether cellular alterations in the DRt persist after opioids are discontinued and hyperalgesia resolves is unknown. Here, we investigated the long-term effects of morphine on DRt MOR expression, signaling, and function after hyperalgesia has been resolved. Methods: Male Wistar rats received morphine for 7 days either subcutaneously or continuously. Nociceptive sensitivity was evaluated by von Frey and hot-plate tests. MOR and phosphorylated CREB (pCREB) expression in the DRt were quantified during OIH and after hyperalgesia resolution. In the post-OIH phase, we evaluated the effects of MOR activation by DAMGO at DRt, postoperative pain behavior, and systemic morphine dose\u2013response curves. Results: Both morphine regimens induced hypersensitivity that subsided within two weeks. MOR expression in the DRt increased during OIH and normalized in the post-OIH phase, whereas pCREB levels remained elevated in both phases. In the post-OIH phase, DAMGO microinjection at the DRt reinstated robust hypersensitivity and systemic morphine showed reduced antiallodynic potency in postoperative pain. Conclusions: Chronic morphine leaves a lasting molecular imprint in the DRt, sustaining excitatory MOR signaling that can reinstate hyperalgesia and likely diminishes later opioid analgesic efficacy.<\/jats:p>","DOI":"10.3390\/ph19050695","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:34:42Z","timestamp":1777458882000},"page":"695","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Persistent Mu-Opioid Receptor Dysregulation in a Pain-Facilitatory Brain Region Reinstates Hyperalgesia After Resolution of Opioid-Induced Hyperalgesia"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9559-200X","authenticated-orcid":false,"given":"Mar\u00edlia","family":"Sousa","sequence":"first","affiliation":[{"name":"Departamento de Biomedicina, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal"},{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8902-3238","authenticated-orcid":false,"given":"Ana Rita","family":"Costa","sequence":"additional","affiliation":[{"name":"Departamento de Biomedicina, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal"},{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, 114 19 Stockholm, Sweden"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5696-1239","authenticated-orcid":false,"given":"Isaura","family":"Tavares","sequence":"additional","affiliation":[{"name":"Departamento de Biomedicina, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal"},{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6797-2558","authenticated-orcid":false,"given":"Isabel","family":"Martins","sequence":"additional","affiliation":[{"name":"Departamento de Biomedicina, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal"},{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/5\/695\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:46:22Z","timestamp":1777459582000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/5\/695"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,28]]},"references-count":0,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ph19050695"],"URL":"https:\/\/doi.org\/10.3390\/ph19050695","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,28]]}}}