{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:49:56Z","timestamp":1790675396280,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T00:00:00Z","timestamp":1601424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["DPA20140129364"],"award-info":[{"award-number":["DPA20140129364"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"name":"IDEX UNiversity of Strasbourg","award":["postdoctoral fellowship"],"award-info":[{"award-number":["postdoctoral fellowship"]}]},{"DOI":"10.13039\/501100004794","name":"Centre national de la Recherche Scientifique","doi-asserted-by":"publisher","award":["na"],"award-info":[{"award-number":["na"]}],"id":[{"id":"10.13039\/501100004794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003768","name":"University of Strasbourg","doi-asserted-by":"publisher","award":["na"],"award-info":[{"award-number":["na"]}],"id":[{"id":"10.13039\/501100003768","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Increasing evidence indicates that native mu and delta opioid receptors can associate to form heteromers in discrete brain neuronal circuits. However, little is known about their signaling and trafficking. Using double-fluorescent knock-in mice, we investigated the impact of neuronal co-expression on the internalization profile of mu and delta opioid receptors in primary hippocampal cultures. We established ligand selective mu\u2013delta co-internalization upon activation by 1-[[4-(acetylamino)phenyl]methyl]-4-(2-phenylethyl)-4-piperidinecarboxylic acid, ethyl ester (CYM51010), [d-Ala2, NMe-Phe4, Gly-ol5]enkephalin (DAMGO), and deltorphin II, but not (+)-4-[(\u03b1R)-\u03b1-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), morphine, or methadone. Co-internalization was driven by the delta opioid receptor, required an active conformation of both receptors, and led to sorting to the lysosomal compartment. Altogether, our data indicate that mu\u2013delta co-expression, likely through heteromerization, alters the intracellular fate of the mu opioid receptor, which provides a way to fine-tune mu opioid receptor signaling. It also represents an interesting emerging concept for the development of novel therapeutic drugs and strategies.<\/jats:p>","DOI":"10.3390\/molecules25194493","type":"journal-article","created":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T09:41:01Z","timestamp":1601458861000},"page":"4493","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Heteromerization of Endogenous Mu and Delta Opioid Receptors Induces Ligand-Selective Co-Targeting to Lysosomes"],"prefix":"10.3390","volume":"25","author":[{"given":"Lyes","family":"Derouiche","sequence":"first","affiliation":[{"name":"French National Centre for Scientific Research, Institut des Neurosciences Cellulaires et Int\u00e9gratives, University of Strasbourg, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Pierre","sequence":"additional","affiliation":[{"name":"French National Centre for Scientific Research, Institut des Neurosciences Cellulaires et Int\u00e9gratives, University of Strasbourg, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Doridot","sequence":"additional","affiliation":[{"name":"French National Centre for Scientific Research, Chronobiotron, 67200 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4359-1157","authenticated-orcid":false,"given":"St\u00e9phane","family":"Ory","sequence":"additional","affiliation":[{"name":"French National Centre for Scientific Research, Institut des Neurosciences Cellulaires et Int\u00e9gratives, University of Strasbourg, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8758-1009","authenticated-orcid":false,"given":"Dominique","family":"Massotte","sequence":"additional","affiliation":[{"name":"French National Centre for Scientific Research, Institut des Neurosciences Cellulaires et Int\u00e9gratives, University of Strasbourg, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1054\/npep.2002.0900","article-title":"Opioid receptor genes inactivated in mice: The highlights","volume":"36","author":"Kieffer","year":"2002","journal-title":"Neuropeptides"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"230","DOI":"10.2174\/138945012799201612","article-title":"Current research on opioid receptor function","volume":"13","author":"Feng","year":"2012","journal-title":"Curr. 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