{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:51:05Z","timestamp":1788922265974,"version":"build-2803163510"},"reference-count":49,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000835","name":"University of Bath","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000835","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":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Nalfurafine is the only clinically approved kappa opioid receptor (KOPr) agonist that can cross the blood\u2013brain barrier and exert CNS effects. Because its clinical use is not associated with dysphoria, it is widely believed to have an atypical pharmacological profile. Nalfurafine's atypical properties are proposed to result from its G\u2010protein\u2010biased KOPr agonist property, leading to the widespread use of nalfurafine as a nonaversive KOPr agonist in preclinical research. The validity of nonaversive claims for nalfurafine was investigated in mice by comparing its antinociceptive and aversive effects with those of the typical, nonbiased KOPr agonist\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.guidetopharmacology.org\/GRAC\/LigandDisplayForward?ligandId=1652\">U50,488<\/jats:ext-link>\n                    in tail withdrawal and conditioned place aversion (CPA) tests. Dose responses for tail withdrawal with nalfurafine and U50,488 were determined in warm (52\u00b0C) water in adult male and female C57BL\/6J mice. Doses of U50,488 produced antinociception from 5\u2009mg\/kg, and doses of nalfurafine from 0.06\u2009mg\/kg. Four\u2010fold lower doses of either KOPr agonist (U50,488: 1.25\u2009mg\/kg; nalfurafine: 0.015\u2009mg\/kg) were subthreshold for antinociception. No sex differences were seen. Antinociceptive effects were fully blocked by the KOPr antagonist norBNI (10\u2009mg\/kg). Antinociceptive doses of nalfurafine (0.06\u2009mg\/kg) and U50,488 (5.0\u2009mg\/kg) both induced CPA. Subantinociceptive doses of nalfurafine (0.015\u2009mg\/kg) and U50,488 (1.25\u2009mg\/kg) were nonaversive in CPA. Thus, in mice, at doses that are antinociceptive, CPA was evident for both KOPr agonists. Neither nalfurafine nor U50,488 showed a separation between their antinociceptive and aversive effects, contradicting the hypothesis that nalfurafine is a nonaversive analgesic in mice. The findings caution against assuming nalfurafine is a nonaversive KOPr agonist for use in preclinical research.\n                  <\/jats:p>","DOI":"10.1002\/prp2.70201","type":"journal-article","created":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T04:12:06Z","timestamp":1764994326000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Nalfurafine is Aversive at Antinociceptive Doses in Mice"],"prefix":"10.1002","volume":"13","author":[{"given":"E. J.","family":"Kuijer","sequence":"first","affiliation":[{"name":"Department of Life Sciences University of Bath  Bath UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. H.","family":"Marinelli","sequence":"additional","affiliation":[{"name":"Department of Life Sciences University of Bath  Bath UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. J.","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Life Sciences University of Bath  Bath UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. J.","family":"Heal","sequence":"additional","affiliation":[{"name":"Department of Life Sciences University of Bath  Bath UK"},{"name":"DevelRx Ltd, BioCity  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Smith","sequence":"additional","affiliation":[{"name":"DevelRx Ltd, BioCity  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Wonnacott","sequence":"additional","affiliation":[{"name":"Department of Life Sciences University of Bath  Bath UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0781-8887","authenticated-orcid":false,"given":"C. P.","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Life Sciences University of Bath  Bath UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.46.366"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005020152"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfp588"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000341268"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0178991"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.12830"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJNRD.S145720"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010022\u201011431\u20101"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/164_2020_400"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.3016896"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph12020095"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.837671"},{"key":"e_1_2_12_14_1","unstructured":"National Library of Medicine \u201cEfficacy and Safety of MT\u20109938 for Treatment of Uremic Pruritus in Subjects With End\u2010Stage Renal Disease Receiving Hemodialysis \u201dhttps:\/\/Clinicaltrials.Gov\/Study\/NCT01660243?intr=TRK\u2010820&rank=6&tab=results."},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/2054358116675345"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aai8441"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3769\u201007.2007"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.9b00195"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2017.01.016"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.118.255661"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.0c00407"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201037041\u20107"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41386\u2010018\u20100155\u20100"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213\u2010020\u201005543\u20107"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2022.173377"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300860"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2444\u201015.2015"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2010.07.038"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2013.07.042"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318\u2010015\u20100286\u20101"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881121991570"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.109.161455"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1121"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16177"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705540200"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0024\u20103205(99)00417\u20108"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.2c00526"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2020.127360"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014\u20102999(99)00815\u20108"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213\u2010021\u201005965\u2010x"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0024\u20103205(01)00957\u20102"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/acer.14033"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.073668"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.02.046"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.12404"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265\u2010021\u201001619\u20106"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213\u2010017\u20104758\u2010747"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.108.143925"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2004.05.033"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2022.173394"}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.70201","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T16:56:26Z","timestamp":1765817786000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.70201"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":49,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/prp2.70201"],"URL":"https:\/\/doi.org\/10.1002\/prp2.70201","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"value":"2052-1707","type":"print"},{"value":"2052-1707","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-05-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70201"}}