{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:55:51Z","timestamp":1792158951741,"version":"4.4.0"},"reference-count":56,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Irinotecan is a widely used chemotherapeutic agent that frequently causes nausea and emesis. Its emetic mechanism of action is poorly understood and the choice of drugs to reduce nausea and emesis is largely empirical.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      Using\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>Suncus murinus<\/jats:italic>\n                      <\/jats:styled-content>\n                      , we examined (i) the dose\u2013response and temporal profile of irinotecan\u2010induced emesis; (ii) emetic potential of its active metabolite, SN\u201038; (iii) involvement of vagal and central pathways; (iv) efficacies of classical antiemetics administered alone, or in combinations. Behavioural, respiratory, metabolic and c\u2010Fos immunohistochemical analyses were used to delineate mechanisms involved in emesis control. A microelectrode array (MEA) system assessed the effects of irinotecan and SN\u201038 on gastrointestinal slow\u2010wave activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Irinotecan induced dose\u2010dependent emesis within 24\u2009h, whereas SN\u201038 was inactive. Neither compound altered respiration. Bilateral abdominal vagotomy attenuated early\u2010phase (0\u20134\u2009h) of irinotecan\u2010induced emesis. Palonosetron suppressed emesis and was the most effective monotherapy; olanzapine alone also showed antiemetic efficacy. Notably, olanzapine\u2010containing combinations with palonosetron and aprepitant or dexamethasone provided superior protection compared with monotherapies. Irinotecan increased c\u2010Fos expression in the brainstem, and hypothalamic and limbic regions; palonosetron selectively reduced brainstem activation. Serum metabolomics revealed reduced tyramine levels and associations between emetic episodes and 5\u2010HT\u2010related pathways. MEA recordings showed that irinotecan, but not SN\u201038, produced selective disruptions of upper\u2010gut rhythmic activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Irinotecan\u2010induced emesis is mediated predominantly through 5\u2010HT\u2083\u2010dependent vagal\u2013brainstem pathways with additional activation of hypothalamic and limbic regions. Altered intestinal pacemaker activity and 5\u2010HT metabolism may contribute to gastrointestinal adverse effects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70702","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:30:33Z","timestamp":1792157433000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigation of the mechanisms and modulation of irinotecan\u2010induced emesis in\n                    <scp>\n                      <i>Suncus murinus<\/i>\n                    <\/scp>"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2340-5274","authenticated-orcid":false,"given":"Zengbing","family":"Lu","sequence":"first","affiliation":[{"name":"Emesis Research Group, School of Biomedical Sciences, Faculty of Medicine The Chinese University of Hong Kong  Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0031-0151","authenticated-orcid":false,"given":"Julia Y. H.","family":"Liu","sequence":"additional","affiliation":[{"name":"Emesis Research Group, School of Biomedical Sciences, Faculty of Medicine The Chinese University of Hong Kong  Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3618-1715","authenticated-orcid":false,"given":"Yasuhiro","family":"Nakagami","sequence":"additional","affiliation":[{"name":"R&amp;D Division Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4565-0619","authenticated-orcid":false,"given":"Zitong","family":"Li","sequence":"additional","affiliation":[{"name":"Emesis Research Group, School of Biomedical Sciences, Faculty of Medicine The Chinese University of Hong Kong  Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5867-4962","authenticated-orcid":false,"given":"Xiaofei","family":"Huang","sequence":"additional","affiliation":[{"name":"Emesis Research Group, School of Biomedical Sciences, Faculty of Medicine The Chinese University of Hong Kong  Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2175-0254","authenticated-orcid":false,"given":"Man P.","family":"Ngan","sequence":"additional","affiliation":[{"name":"Emesis Research Group, School of Biomedical Sciences, Faculty of Medicine The Chinese University of Hong Kong  Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8998-1120","authenticated-orcid":false,"given":"Dexuan","family":"Cui","sequence":"additional","affiliation":[{"name":"Emesis Research Group, School of Biomedical Sciences, Faculty of Medicine The Chinese University of Hong Kong  Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8316-0792","authenticated-orcid":false,"given":"John A.","family":"Rudd","sequence":"additional","affiliation":[{"name":"Emesis Research Group, School of Biomedical Sciences, Faculty of Medicine The Chinese University of Hong Kong  Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70234"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/nutrit\/nuy036"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(87)90100-6"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15852"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(96)00275-0"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.18.1024"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2013.08.047"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(23)00628-9"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14987"},{"key":"e_1_2_12_11_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.neuropharm.2013.01.013","article-title":"Separation of emetic and anorexic responses of exendin\u20104, a GLP\u20101 receptor agonist in Suncus murinus (house musk shrew)","volume":"70","author":"Chan S. W.","year":"2013","journal-title":"Neuropharmacology"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.03.016"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.npep.2008.05.002"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01535760"},{"key":"e_1_2_12_15_1","first-page":"303","article-title":"2016 updated MASCC\/ESMO consensus recommendations: Prevention of nausea and vomiting following multiple\u2010day chemotherapy, high\u2010dose chemotherapy, and breakthrough nausea and vomiting","volume":"25","author":"Einhorn L. H.","year":"2017","journal-title":"Support Care Cancer"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-1838(98)00028-9"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctarc.2020.100278"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-011-1286-6"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.01296"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1006\/frne.1993.1006"},{"key":"e_1_2_12_21_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/978-3-319-34076-0_2","volume-title":"Nausea and Vomiting: Diagnosis and Treatment","author":"Horn C. C.","year":"2017"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00413.2013"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2025.08.003"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.2535\/ofaj1936.75.1_9"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2013.776541"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-015-2990-4"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042-7158.1993.tb05573.x"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-7843.2007.00068.x"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)10353-4"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15178"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108580"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2019.05.002"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1109\/EMBC46164.2021.9630494"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12938-022-01012-8"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00391"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-023-08225-0"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2023.1077207"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1515725"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1159\/000227634"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-84225-6"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.26076"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-010-1339-4"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2009.08.075"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pathophys.2017.07.002"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00869"},{"issue":"2","key":"e_1_2_12_47_1","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0014-2999(98)00920-0","article-title":"Inhibition of emesis by tachykinin NK1 receptor antagonists in Suncus murinus (house musk shrew)","volume":"366","author":"Rudd J. A.","year":"1999","journal-title":"European Journal of Pharmacology"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-2999(03)01863-6"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.820398"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-023-08222-3"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-024-05712-7"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.746053"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00412"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2005.01.005"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.23685"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.750507"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22115797"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.70702","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bph.70702","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.70702","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:30:35Z","timestamp":1792157435000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.70702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,16]]},"references-count":56,"alternative-id":["10.1111\/bph.70702"],"URL":"https:\/\/doi.org\/10.1111\/bph.70702","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,16]]},"assertion":[{"value":"2026-02-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"bph.70702"}}