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.