{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:47:18Z","timestamp":1792133238809,"version":"4.4.0"},"reference-count":75,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DA036061"],"award-info":[{"award-number":["DA036061"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DA037161"],"award-info":[{"award-number":["DA037161"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DA037743"],"award-info":[{"award-number":["DA037743"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DA046122"],"award-info":[{"award-number":["DA046122"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp;amp; Perspec"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Opioid receptor antagonists increase the plasma membrane density of \u03bc\u2010opioid receptors (MOR) in\u00a0vivo, thereby inducing \u201csupersensitivity\u201d to opioid agonists. This phenomenon increases the risk of overdose in patients that were being treated with naltrexone (Ntx), a popular MOR antagonist. Although there are many studies on the effects of ligands on the plasma membrane density of MORs, their effects on MOR trafficking from the endoplasmic reticulum (ER) via endoplasmic reticulum exit sites (ERES) have not been investigated. Using fluorescently tagged Sec24 to visualize ERES and a highly ER\u2010retained \u03bc\u2010opioid receptor (MOR) point mutant, MOR[N190K], we measured ERES levels after incubation in various opioid receptor ligands. Data from sensitized emission F\u00f6rster resonance energy transfer (FRET) show that MOR[N190K] interacts with Sec24D. We observe that Ntx, naloxone, morphine, and fentanyl increase the fraction of the cytoplasm occupied by ERES. In contrast, buprenorphine, methadone, and two allosteric modulators have no substantial effect on ERES levels. Mutating S375, an important phosphorylation site for MOR internalization, decreased morphine and fentanyl's pharmacological chaperoning abilities but did not affect Ntx's pharmacological chaperoning abilities. Ntx did not change intracellular cyclic adenosine monophosphate (cAMP) concentrations, so global trafficking is not expected to change. We also find that antagonist\u2010induced pharmacological chaperoning depends on retrotransport from the Golgi as brefeldin A (BFA) treatment prevented pharmacological chaperoning. These data reveal new understandings of how opioid ligands change MOR trafficking from the ER and can help us better understand the pathophysiology of opioid use disorder.<\/jats:p>","DOI":"10.1002\/prp2.70315","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:58:09Z","timestamp":1789657089000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Naltrexone, Naloxone, Morphine, and Fentanyl Pharmacologically Chaperone a Mutant \u03bc\u2010Opioid Receptor via an Endoplasmic Reticulum Exit Site\u2010Dependent Pathway"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0923-8886","authenticated-orcid":false,"given":"Stephen N.","family":"Grant","sequence":"first","affiliation":[{"name":"Division of Chemistry and Chemical Engineering California Institute of Technology  Pasadena California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Mulcahy","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering California Institute of Technology  Pasadena California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry A.","family":"Lester","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering California Institute of Technology  Pasadena California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.53.3.377"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2025.1597922"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12653"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2008.09.023"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/syn.10246"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.108.054064"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2006.11.003"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.17.9241"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.112.005942"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2007.10.004"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.01388"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26051862"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2013.12.001"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.127019"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006\u20108993(82)90811\u20103"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006\u20108993(83)90023\u20109"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2019.02.031"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.107.043471"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306\u20104522(03)00135\u20100"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23214"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.02.045"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.01.035"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1151\/spp021113"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M610896200"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2014.01.005"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2012.00137"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.6b00195"},{"key":"e_1_2_12_29_1","first-page":"135","volume-title":"Targeting Trafficking in Drug Development","author":"Leidenheimer N. J.","year":"2018"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.2393\u201013.2013"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.7.1628"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI8688"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2009.11.003"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.110.064188"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201010532"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4194\u201015.2016"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.013383"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.2304\u201011.2011"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.112.082875"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.115.098244"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2015.07.025"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2008.0381.focus"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms130810022"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.112.077792"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.749119"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035\u2010015\u20100041\u20101"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)38093-6"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)22512-5"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M201869200"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031\u2010013\u20100019\u20103"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41537\u2010024\u201000498\u20106"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2025.10.046"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines13071774"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.112.007138"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.64.1.32"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M009571200"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi0100945"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476\u20105381.2008.00035.x"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092\u20108674(94)90138\u20104"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.113.12.2177"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.embor942"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.209890"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201311102"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.18.13727"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.007370"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI140311"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010009\u20109090\u20107"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.1c00524"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1245321"},{"key":"e_1_2_12_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.11.028"},{"key":"e_1_2_12_71_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi701436w"},{"key":"e_1_2_12_72_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.108.048512"},{"key":"e_1_2_12_73_1","doi-asserted-by":"publisher","DOI":"10.1177\/1744806918769492"},{"key":"e_1_2_12_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2015.01.022"},{"key":"e_1_2_12_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/0091\u20103057(94)00375\u2010s"},{"key":"e_1_2_12_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2004.07.052"}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.70315","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/prp2.70315","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.70315","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:14:59Z","timestamp":1792131299000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.70315"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":75,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/prp2.70315"],"URL":"https:\/\/doi.org\/10.1002\/prp2.70315","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"value":"2052-1707","type":"print"},{"value":"2052-1707","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]},"assertion":[{"value":"2025-09-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70315"}}