{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:48:51Z","timestamp":1788922131424,"version":"build-2803163510"},"reference-count":30,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":344,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003524","name":"Ministry of Business, Innovation and Employment","doi-asserted-by":"publisher","award":["RTVU1802"],"award-info":[{"award-number":["RTVU1802"]}],"id":[{"id":"10.13039\/501100003524","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin &amp; Trans Imm"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Multiple sclerosis is an immune\u2010mediated inflammatory disease of the central nervous system. Recently, kappa opioid receptor (KOR) agonists were found to promote remyelination and recovery in models of demyelination. However, the side effects of many full KOR agonists limit clinical use. Activation of KOR and mu opioid receptors (MOR) often has opposing effects. Therefore, it is plausible that activating KOR and antagonising MOR may confer a beneficial increase in therapeutic efficacy at lower doses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study investigated the hypothesis that combining the clinically available full KOR agonist nalfurafine (NalF) with a MOR antagonist\/partial KOR agonist nalmefene (NalM) would provide greater than additive benefits in the murine model of immune\u2010driven demyelination, experimental autoimmune encephalomyelitis (EAE).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that NalM alone reduced EAE disease severity when administered therapeutically although NalM at the most effective doses did not enhance myelination or reduce lesions in the spinal cord. Moreover, a combination of NalF\/NalM at suboptimal doses significantly reduced lesion size and promoted myelination in the spinal cord suggesting a better\u2010than\u2010additive effect on lesion resolution. This finding was supported by a bioinformatic analysis response that highlighted the myelination benefits of the suboptimal dose combination while the optimal dose combination of NalF\/NalM stimulated increased immunomodulatory activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Findings from this study indicate that the remyelinating and immunomodulatory effects of the KOR agonist NalF can be significantly enhanced through interactions with the MOR antagonist NalM in a distinct dose\u2010dependent manner.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cti2.70069","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T07:56:37Z","timestamp":1765526197000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nalmefene enhances the remyelinating ability of nalfurafine when administered therapeutically at very low doses during experimental autoimmune encephalomyelitis"],"prefix":"10.1002","volume":"14","author":[{"given":"Lisa","family":"Denny","sequence":"first","affiliation":[{"name":"School of Biological Sciences Victoria University of Wellington  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Robichon","sequence":"additional","affiliation":[{"name":"School of Biological Sciences Victoria University of Wellington  Wellington New Zealand"},{"name":"Centre for Biodiscovery Victoria University of Wellington  Wellington New Zealand"},{"name":"Department of Pathology and Molecular Medicine University of Otago  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki","family":"Templeton","sequence":"additional","affiliation":[{"name":"School of Biological Sciences Victoria University of Wellington  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mackenzie","family":"Kiernan","sequence":"additional","affiliation":[{"name":"School of Biological Sciences Victoria University of Wellington  Wellington New Zealand"},{"name":"Centre for Biodiscovery Victoria University of Wellington  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E","family":"Prisinzano","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Kentucky  Lawrence Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bronwyn M","family":"Kivell","sequence":"additional","affiliation":[{"name":"School of Biological Sciences Victoria University of Wellington  Wellington New Zealand"},{"name":"Centre for Biodiscovery Victoria University of Wellington  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2344-7281","authenticated-orcid":false,"given":"Anne Camille","family":"La Flamme","sequence":"additional","affiliation":[{"name":"School of Biological Sciences Victoria University of Wellington  Wellington New Zealand"},{"name":"Centre for Biodiscovery Victoria University of Wellington  Wellington New Zealand"},{"name":"Malaghan Institute of Medical Research  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.23.021704.115707"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0502-500"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e328300c70d"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1134\/S0006297914050034"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-010-1819-6"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-420118-7.00012-3"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13042"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aai8441"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2012.693164"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1234"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.782190"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24583"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11120"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1493-16.2016"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-7843.2008.00306.x"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.120.000134"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1159\/000341268"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJNRD.S145720"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e318238bba6"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/1947601912440575"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.2147\/SAR.S45666"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2011.02.012"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300811"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0736-4679(98)00019-5"},{"key":"e_1_2_10_26_1","first-page":"30","article-title":"Nor\u2010binaltorphimine: a potent and selective kappa\u2010opioid receptor antagonist with long\u2010lasting activity in vivo","volume":"316","author":"Endoh T","year":"1992","journal-title":"Arch Int Pharmacodyn Ther"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705540200"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.18246"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3618"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1480"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02925-4"}],"container-title":["Clinical &amp; Translational Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cti2.70069","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T08:39:45Z","timestamp":1766479185000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cti2.70069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":30,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1002\/cti2.70069"],"URL":"https:\/\/doi.org\/10.1002\/cti2.70069","archive":["Portico"],"relation":{},"ISSN":["2050-0068","2050-0068"],"issn-type":[{"value":"2050-0068","type":"print"},{"value":"2050-0068","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]},"assertion":[{"value":"2025-06-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70069"}}