{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T15:24:30Z","timestamp":1786202670044,"version":"build-2736575974"},"reference-count":68,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T00:00:00Z","timestamp":1711324800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100015515","name":"Kementerian Pendidikan Malaysia","doi-asserted-by":"publisher","award":["FRGS\/1\/2020\/SKK0\/USM\/02\/5"],"award-info":[{"award-number":["FRGS\/1\/2020\/SKK0\/USM\/02\/5"]}],"id":[{"id":"10.13039\/501100015515","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004595","name":"Universiti Sains Malaysia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Kratom is a preparation from <jats:italic>Mitragyna speciosa<\/jats:italic>, which is used as a natural drug preparation for many purposes around the world. However, an overdose of Kratom may cause addiction\u2010like problems including aversive withdrawal states resulting in cognitive impairments via unknown mechanisms. Its main psychoactive alkaloid is mitragynine, showing opioid\u2010like properties.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Here, we analysed the neuropharmacological effects of mitragynine compared with morphine withdrawal in rats and searched for a pharmacological treatment option that may reverse the occurring cognitive deficits that usually aggravate withdrawal.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We found that withdrawal from 14\u2010day mitragynine (1\u201310\u00a0mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>) treatment caused dose\u2010dependent behavioural withdrawal signs resembling those of <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.guidetopharmacology.org\/GRAC\/LigandDisplayForward?ligandId=1627\">morphine<\/jats:ext-link> (5\u00a0mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>) withdrawal. However, mitragynine (5 and 10\u00a0mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>) withdrawal also induced impairments in a passive avoidance task. Mitragynine withdrawal not only reduced hippocampal field excitatory postsynaptic potential (fEPSP) amplitudes in basal synaptic transmission and long\u2010term potentiation (LTP) but also reduced epigenetic markers, such as histone H3K9 and H4K12 expression. At the same time, it up\u2010regulates HDAC2 expression. Targeting the epigenetic adaptations with the <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.guidetopharmacology.org\/GRAC\/FamilyDisplayForward?familyId=848\">HDAC<\/jats:ext-link> inhibitor, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.guidetopharmacology.org\/GRAC\/LigandDisplayForward?ligandId=6852\">SAHA<\/jats:ext-link>, reversed the effects of mitragynine withdrawal on epigenetic dysregulation, hippocampal input\/output curves, paired\u2010pulse facilitation, LTP and attenuated the cognitive deficit. However, SAHA amplified the effects of morphine withdrawal.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>The data from this work show that changes in histone expression and downstream hippocampal plasticity may explain mitragynine, but not morphine, withdrawal behaviours and cognitive impairments. Thus, it may provide a new treatment approach for aversive Kratom\/mitragynine withdrawal and addiction.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16352","type":"journal-article","created":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T07:10:30Z","timestamp":1711350630000},"page":"2070-2084","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mitragynine (Kratom)\u2014Withdrawal behaviour and cognitive impairments can be ameliorated by an epigenetic mechanism"],"prefix":"10.1111","volume":"181","author":[{"given":"Suleiman","family":"Yunusa","sequence":"first","affiliation":[{"name":"Centre for Drug Research Universiti Sains Malaysia  Penang Malaysia"},{"name":"Department of Pharmacology Bauchi State University Gadau  Bauchi State Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian P.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Centre for Drug Research 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