Long-term ketamine administration induces bladder damage and upregulates autophagy-associated proteins in bladder smooth muscle tissue.

Long-term ketamine abuse can cause significant lower urinary tract symptoms in humans, termed ketamine-associated cystitis (KC). Here, we established a model of long-term (6 months) ketamine administration in wild-type (C57BL/6) mice. We elucidated the pathological effects of ketamine in the bladder and investigated changes in autophagy-associated protein expression (i.e., LC3, Beclin-1, and P62) and inflammatory cytokines (i.e., IL-6 and IL-1β) in the bladder smooth muscle tissue. Long-term ketamine administration reduced the number of layers in the bladder mucosal epithelial cells (4-5 layers in the saline group vs. 2-3 layers in the ketamine groups), but increased the number of mast cells and collagen fibers. LC3-II/LC3-I, Beclin-1, IL-6, and IL-1β protein expression in the bladder smooth muscle tissues of ketamine-treated mice was significantly increased. The mRNA and protein levels of P62 in the Ket-60 mg/kg group were also significantly increased, but not the Ket-30 mg/kg group. Our results reveal that long-term ketamine administration can cause cystitis-like pathological changes in mice, and the disordered autophagy in the bladder tissue may be involved in the persistent bladder damage following long-term administration of ketamine at 60 mg/kg.