Using a rat model to translate and explore the pathogenesis of ketamine-induced cystitis

Purpose: Ketamine abusers may develop severe ulcerative cystitis along with irritative bladder symptoms. A reliable animal model may benefit the understanding of pathophysiologies and the development of therapeutic strategies for ketamine-induced cystitis (KIC). We used a popular rat model of KIC to validate the micturition behavior, functional brain images, and possible molecular mechanisms of this model. Materials and Methods: Female Sprague–Dawley rats were distributed to control (saline) and ketamine-treated rats (25 mg/kg/day for 28 days). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Potential bladder transcripts involved in KIC were screened by using next-generation sequencing. Results: In contrast to the control, the ketamine-treated rats developed bladder overactivity accompanied by enhanced fMRI signals in periaqueduct and caudal putamen areas. Alterations in bladder transcripts, including eleven genes involving in regulating NF-κB signaling of bladder inflammation, and Crhr2 gene overexpression associating with vascular endothelial growth factor signaling of bladder ischemia were found in ketamine-treated rats. Both categories could be attributed to neurogenic inflammation induced by the direct toxicity of urinary ketamine and its metabolites. Conclusion: Our study results suggest this animal model could mimic irritative bladder symptoms associated with central sensitization in KIC. Through the bladder transcripts analysis, we highlight the neurogenic inflammation underlying the pathophysiologies of KIC in rats.