{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T12:40:16Z","timestamp":1792586416513,"version":"4.5.0"},"reference-count":23,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neurourology and Urodynamics"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Ketamine\u2011induced cystitis (KIC) is a severe complication of chronic ketamine misuse, yet the underlying mechanisms remain poorly understood. Established rodent models have demonstrated variable changes in voiding behavior and bladder histology, without exploring the sensory mechanisms underlying altered voiding and pain at all. This study aimed to establish a murine model of chronic ketamine\u2010induced cystitis to investigate changes in pain behavior and sensory signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Male and female C57BL\/6\u2009J mice received intraperitoneal ketamine (100\u2009mg\/kg,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200920) or saline (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200920) for 12 weeks. Urine and plasma ketamine, norketamine, and dehydronorketamine concentrations were determined using LC\u2010QTOF\/MS. Voiding behavior was assessed fortnightly using spontaneous voiding assays, suprapubic mechanical sensitivity was evaluated using von Frey filaments, and wellbeing was assessed using nesting and open field assays. Finally, histopathological analysis was performed on bladder and kidney tissues.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Despite high urinary and plasma concentrations of ketamine, norketamine, and dehydronorketamine, ketamine\u2010treated mice showed no significant differences in voiding behavior, suprapubic sensitivity, natural behavior, or bladder and kidney histopathology compared with controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Chronic high\u2010dose ketamine treatment did not induce a robust phenotype of ketamine\u2010induced cystitis in C57BL\/6\u2009J mice, highlighting limitations of using rodent models for recapitulating human ketamine\u2011induced cystitis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/nau.70483","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T11:48:21Z","timestamp":1792583301000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chronic High\u2010Dose Ketamine Fails to Induce a Cystitis\u2010Like Phenotype in Mice Despite High Urinary Metabolite Levels"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2866-4078","authenticated-orcid":false,"given":"Jill","family":"Dewez","sequence":"first","affiliation":[{"name":"VIB\u2010KU Leuven Center for Brain and Disease Research Leuven Belgium"},{"name":"Laboratory of Ion Channel Research (LICR), Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashlee","family":"Caldwell","sequence":"additional","affiliation":[{"name":"VIB\u2010KU Leuven Center for Brain and Disease Research Leuven Belgium"},{"name":"Laboratory of Ion Channel Research (LICR), Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Schillebeeckx","sequence":"additional","affiliation":[{"name":"VIB\u2010KU Leuven Center for Brain and Disease Research Leuven Belgium"},{"name":"Laboratory of Ion Channel Research (LICR), Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot","family":"De Vis","sequence":"additional","affiliation":[{"name":"Unit of Toxicology and Pharmacology, KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5801-1621","authenticated-orcid":false,"given":"Sylvia","family":"Jo\u00e3o Poseiro Coutinho Pinto","sequence":"additional","affiliation":[{"name":"VIB\u2010KU Leuven Center for Brain and Disease Research Leuven Belgium"},{"name":"Laboratory of Ion Channel Research (LICR), Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1691-9930","authenticated-orcid":false,"given":"Evy","family":"Van Den Broek","sequence":"additional","affiliation":[{"name":"VIB\u2010KU Leuven Center for Brain and Disease Research Leuven Belgium"},{"name":"Laboratory of Ion Channel Research (LICR), Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2809-6325","authenticated-orcid":false,"given":"V\u00e9ronique","family":"Hendrickx","sequence":"additional","affiliation":[{"name":"VIB\u2010KU Leuven Center for Brain and Disease Research Leuven Belgium"},{"name":"Laboratory of Ion Channel Research (LICR), Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrien","family":"Luyten","sequence":"additional","affiliation":[{"name":"Laboratory of Implantation, Placentation &amp; Pregnancy Research (POPPY), Department of Development and Regeneration KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcella","family":"Baldewijns","sequence":"additional","affiliation":[{"name":"Department of Pathology University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1778-6022","authenticated-orcid":false,"given":"Jan","family":"Tytgat","sequence":"additional","affiliation":[{"name":"Unit of Toxicology and Pharmacology, KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5526-5821","authenticated-orcid":false,"given":"Thomas","family":"Voets","sequence":"additional","affiliation":[{"name":"VIB\u2010KU Leuven Center for Brain and Disease Research Leuven Belgium"},{"name":"Laboratory of Ion Channel Research (LICR), Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3157-7115","authenticated-orcid":false,"given":"Wouter","family":"Everaerts","sequence":"additional","affiliation":[{"name":"Laboratory of Ion Channel Research (LICR), Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium"},{"name":"Department of Urology University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,21]]},"reference":[{"issue":"1","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.brainresbull.2016.05.016","article-title":"Ketamine Abuse Potential and Use Disorder","volume":"126","author":"Liu Y.","year":"2016","journal-title":"Brain Research Bulletin"},{"key":"e_1_2_10_3_1","unstructured":"Agency EUD \u201cEuropean Drug Report 2026: Trends and Developments \u201d 2026 https:\/\/www.euda.europa.eu\/publications\/european-drug-report\/2026_en."},{"issue":"11","key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1111\/j.1464-410X.2012.11028.x","article-title":"The Prevalence and Natural History of Urinary Symptoms Among Recreational Ketamine Users","volume":"110","author":"Winstock A. R.","year":"2012","journal-title":"BJU International"},{"issue":"4","key":"e_1_2_10_5_1","article-title":"Ketamine\u2010Associated Uropathy During Therapeutic and Nontherapeutic Use: Prevalence, Clinical Features, Mechanisms, and Strategies for Risk Reduction","volume":"86","author":"Andrade C.","year":"2025","journal-title":"Journal of Clinical Psychiatry"},{"issue":"2","key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"128","DOI":"10.5213\/inj.1732704.352","article-title":"The Risk of Upper Urinary Tract Involvement in Patients With Ketamine\u2010Associated Uropathy","volume":"21","author":"Yee C. H.","year":"2017","journal-title":"International Neurourology Journal"},{"issue":"3","key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1002\/nau.25148","article-title":"Current Approaches for the Treatment of Ketamine\u2010Induced Cystitis","volume":"42","author":"Zhou J.","year":"2023","journal-title":"Neurourology and Urodynamics"},{"issue":"5","key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3109\/21681805.2014.909530","article-title":"Ketamine Cystitis: Practical Considerations in Management","volume":"48","author":"Misra S.","year":"2014","journal-title":"Scandinavian Journal of Urology"},{"issue":"10","key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1111\/add.70073","article-title":"The Landscape of Ketamine Use Disorder: Patient Experiences and Perspectives on Current Treatment Options","volume":"120","author":"Harding R. E.","year":"2025","journal-title":"Addiction"},{"issue":"9","key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1111\/iju.12841","article-title":"Possible Pathophysiology of Ketamine\u2010Related Cystitis and Associated Treatment Strategies","volume":"22","author":"Jhang J. F.","year":"2015","journal-title":"International Journal of Urology"},{"issue":"3","key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1002\/nau.25612","article-title":"Can We Better Understand, Diagnose, and Treat Ketamine\u2010Induced Uropathy, and Can It Be Reversed? Ici\u2010Rs 2024","volume":"44","author":"Herv\u00e9 F.","year":"2025","journal-title":"Neurourology and Urodynamics"},{"issue":"7","key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1002\/nau.24763","article-title":"Rodent Models of Ketamine\u2010Induced Cystitis","volume":"40","author":"Sultana S.","year":"2021","journal-title":"Neurourology and Urodynamics"},{"issue":"1","key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3390\/ijms23010107","article-title":"TRPM3 Is Expressed in Afferent Bladder Neurons and Is Upregulated During Bladder Inflammation","volume":"23","author":"Vanneste M.","year":"2021","journal-title":"International Journal of Molecular Sciences"},{"issue":"12","key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.1097\/j.pain.0000000000003738","article-title":"A Catheter\u2010Associated Urinary Tract Infection Mouse Model to Study Bladder Dysfunction and Pain","volume":"166","author":"Schillebeeckx L.","year":"2025","journal-title":"Pain"},{"issue":"6","key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"451","DOI":"10.30802\/AALAS-CM-19-000042","article-title":"A Review of Pain Assessment Methods in Laboratory Rodents","volume":"69","author":"Turner P. V.","year":"2019","journal-title":"Comparative Medicine"},{"issue":"6","key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1007\/s13577-023-00972-w","article-title":"Circ\u2010SFMBT2 Sponges miR\u2010224\u20105p to Induce Ketamine\u2010Induced Cystitis by Up\u2010Regulating Metadherin (Mtdh)","volume":"36","author":"Zeng F.","year":"2023","journal-title":"Human Cell"},{"issue":"4","key":"e_1_2_10_17_1","first-page":"2716","article-title":"Ketamine\u2011Induced Bladder Dysfunction Is Associated With Extracellular Matrix Accumulation and Impairment of Calcium Signaling in a Mouse Model","volume":"19","author":"Shen C. H.","year":"2019","journal-title":"Molecular Medicine Reports"},{"issue":"4","key":"e_1_2_10_18_1","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.3892\/etm.2017.4913","article-title":"Changes to the Bladder Epithelial Barrier Are Associated With Ketamine\u2010Induced Cystitis","volume":"14","author":"Duan Q.","year":"2017","journal-title":"Experimental and Therapeutic Medicine"},{"issue":"9","key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"F885","DOI":"10.1152\/ajprenal.00483.2015","article-title":"Intact Urothelial Barrier Function in a Mouse Model of Ketamine\u2010Induced Voiding Dysfunction","volume":"310","author":"Rajandram R.","year":"2016","journal-title":"American Journal of Physiology\u2010Renal Physiology"},{"issue":"3","key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.3892\/mmr.2016.5482","article-title":"Evaluation of Urinary Bladder Fibrogenesis in a Mouse Model of Long\u2010Term Ketamine Injection","volume":"14","author":"Shen C. 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H.","year":"2015","journal-title":"Molecular Medicine Reports"},{"issue":"12","key":"e_1_2_10_24_1","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1002\/tox.23365","article-title":"Long\u2010Term Ketamine Administration Induces Bladder Damage and Upregulates Autophagy\u2010Associated Proteins in Bladder Smooth Muscle Tissue","volume":"36","author":"Li Y.","year":"2021","journal-title":"Environmental Toxicology"}],"container-title":["Neurourology and Urodynamics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/nau.70483","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/nau.70483","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/nau.70483","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T11:48:25Z","timestamp":1792583305000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/nau.70483"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,21]]},"references-count":23,"alternative-id":["10.1002\/nau.70483"],"URL":"https:\/\/doi.org\/10.1002\/nau.70483","archive":["Portico"],"relation":{},"ISSN":["0733-2467","1520-6777"],"issn-type":[{"value":"0733-2467","type":"print"},{"value":"1520-6777","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,21]]},"assertion":[{"value":"2026-08-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"nau.70483"}}