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.

中文翻译：

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长期服用氯胺酮诱导膀胱损伤并上调膀胱平滑肌组织中的自噬相关蛋白

长期滥用氯胺酮会导致人类出现明显的下尿路症状，称为氯胺酮相关性膀胱炎 (KC)。在这里，我们在野生型 (C57BL/6) 小鼠中建立了长期（6 个月）氯胺酮给药模型。我们阐明了氯胺酮在膀胱中的病理作用，并研究了膀胱平滑肌中自噬相关蛋白表达（即 LC3、Beclin-1 和 P62）和炎性细胞因子（即 IL-6 和 IL-1β）的变化组织。长期服用氯胺酮减少了膀胱粘膜上皮细胞的层数（盐水组为 4-5 层，氯胺酮组为 2-3 层），但增加了肥大细胞和胶原纤维的数量。LC3-II/LC3-I、Beclin-1、IL-6、氯胺酮处理小鼠膀胱平滑肌组织中 IL-1β 蛋白表达显着增加。Ket-60 mg/kg 组中 P62 的 mRNA 和蛋白质水平也显着增加，但 Ket-30 mg/kg 组没有。我们的研究结果表明，长期服用氯胺酮可引起小鼠膀胱炎样病变，膀胱组织自噬紊乱可能与长期服用氯胺酮 60 mg/kg 后持续性膀胱损伤有关。