Chronic High‐Dose Ketamine Fails to Induce a Cystitis‐Like Phenotype in Mice Despite High Urinary Metabolite Levels

Aims Ketamine‑induced 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‐induced cystitis to investigate changes in pain behavior and sensory signaling. Methods Male and female C57BL/6 J mice received intraperitoneal ketamine (100 mg/kg, n = 20) or saline ( n = 20) for 12 weeks. Urine and plasma ketamine, norketamine, and dehydronorketamine concentrations were determined using LC‐QTOF/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. Results Despite high urinary and plasma concentrations of ketamine, norketamine, and dehydronorketamine, ketamine‐treated mice showed no significant differences in voiding behavior, suprapubic sensitivity, natural behavior, or bladder and kidney histopathology compared with controls. Conclusion Chronic high‐dose ketamine treatment did not induce a robust phenotype of ketamine‐induced cystitis in C57BL/6 J mice, highlighting limitations of using rodent models for recapitulating human ketamine‑induced cystitis.