{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:49:28Z","timestamp":1788922168575,"version":"build-2803163510"},"reference-count":27,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T00:00:00Z","timestamp":1756252800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Typical prescribed opioids are known to inhibit intestinal transit and induce emesis\u2010like behaviors in animals via distinct mechanisms and varying magnitudes. However, there is limited evidence regarding whether atypical opioids also produce these adverse effects in animals. This study was designed to investigate whether tramadol, its active metabolite O\u2010desmethyltramadol (M1), and methadone cause such side effects and to elucidate their underlying mechanisms. In ferrets, methadone and M1\u2014but not tramadol and oxycodone\u2014elicited adverse effects including emesis and tremor. Notably, the adverse effects associated with high\u2010dose methadone required urgent intervention with naloxone, indicating a more severe toxicity profile. The severity of emesis followed the rank order: M1\u2009&gt;\u2009methadone. In contrast to previous findings with morphine, M1\u2010induced retching was significantly inhibited by the selective dopamine D\n                    <jats:sub>2<\/jats:sub>\n                    receptor antagonist prochlorperazine, but not by the atypical antipsychotic olanzapine, suggesting a distinct receptor\u2010specific modulation. In mice, both methadone and high\u2010dose M1 significantly suppressed gastrointestinal transit. Notably, suppressed gastrointestinal transit induced by methadone and M1 exhibited different region\u2010specific mechanisms. Taken together with previous findings, the present results suggest that adverse effects caused by atypical opioids and those caused by typical opioids differ both mechanistically and pharmacologically. Recognizing these distinct profiles is essential for evaluating opioid\u2010induced adverse effects and can help refine clinical strategies. Ultimately, these insights may contribute to the development of evidence\u2010based interventions aimed at minimizing opioid\u2010related complications and improving the quality of life for patients receiving opioid\u2010based pain therapies.\n                  <\/jats:p>","DOI":"10.1002\/jat.4912","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T02:39:32Z","timestamp":1756348772000},"page":"551-559","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Emesis and Constipation Induced by Methadone and the Active Metabolite of Tramadol (M1) in Animals"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7751-0231","authenticated-orcid":false,"given":"Tomohisa","family":"Mori","sequence":"first","affiliation":[{"name":"Department of Toxicology Hoshi University School of Pharmacy and Pharmaceutical Sciences  Tokyo Japan"},{"name":"Laboratory on Mechanistic Control of Behavioral Plasticity Hoshi University School of Pharmacy and Pharmaceutical Sciences  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Shibasaki","sequence":"additional","affiliation":[{"name":"Department of Toxicology Hoshi University School of Pharmacy and Pharmaceutical Sciences  Tokyo Japan"},{"name":"Laboratory of Tissue Regeneration Hoshi University School of Pharmacy and Pharmaceutical Sciences  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Fukuma","sequence":"additional","affiliation":[{"name":"Department of Toxicology Hoshi University School of Pharmacy and Pharmaceutical Sciences  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Uzawa","sequence":"additional","affiliation":[{"name":"Department of Toxicology Hoshi University School of Pharmacy and Pharmaceutical Sciences  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Toxicology Hoshi University School of Pharmacy and Pharmaceutical Sciences  Tokyo Japan"},{"name":"Pharmacology Laboratory, Pharmaceutical Department Shonan University of Medical Sciences  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,27]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0028\u20103908(91)90136\u2010y"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300525200"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e318164cf9e"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)10630-7"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2003.08.027"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/1744806916654146"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476\u20105381.1957.tb01354.x"},{"issue":"6","key":"e_1_2_9_9_1","first-page":"877","article-title":"Receptor Binding, Analgesic and Antitussive Potency of Tramadol and Other Selected Opioids","volume":"38","author":"Hennies H. 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