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Long-term ketamine abuse induces cystitis in rats by impairing the bladder epithelial barrier

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Abstract

Long-term ketamine abuse is known to affect the lower urinary tract and produce symptoms of cystitis. However, the pathophysiology and causative mechanism of the changes in bladder function remain unclear. The present study aimed to investigate the existence of ketamine-induced cystitis in a rat model and characterize the underlining mechanisms. Rats were assigned to blank control, normal saline (NS), low-dose ketamine (LK, 5 mg/kg), and high-dose ketamine (HK, 50 mg/kg) groups. The two experimental groups received ketamine hydrochloride daily for 16 weeks. All rats were housed individually for assessment of urinary frequency and urine volume. Urinary biomarkers were measured at different time points. Rat bladders were excised for histopathology, immunohistochemistry, and western blot analysis. Ketamine-treated rats had increased urinary frequency compared to NS-treated rats at Week 16. Urinary nitric oxide and antiproliferative factor levels were increased in ketamine-treated rats within the first 30 h after administration. After long-term ketamine administration, urinary glycoprotein GP51 and potassium levels were decreased in the HK and LK groups compared to the NS group. Ketamine-treated rats showed thickened bladder epithelial layer, increased expression of inducible nitric oxide synthase and occludin, and decreased expression of zonula occludens-1 in the bladder wall. Ketamine, or its urinary metabolites, disrupted the proliferation of bladder epithelial cells, resulting in defected bladder epithelial barrier. Subsequent leakage of urinary potassium causes a stress response in the bladder and provokes cystitis.

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Acknowledgments

The authors thank Dr. Paul Fraser for revising the manuscript. This work was supported by the National Nature Science Foundation of China (Grant No. 81100540), the Guangdong Natural Science Foundation (Grant No. S2012010008919 and S2013010014890).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China

    Di Gu, Jun Huang, Youle Yin, Zhengfei Shan, Shaobin Zheng & Peng Wu

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  1. Di Gu
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  2. Jun Huang
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  3. Youle Yin
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  4. Zhengfei Shan
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  5. Shaobin Zheng
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Correspondence to Shaobin Zheng or Peng Wu.

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Gu, D., Huang, J., Yin, Y. et al. Long-term ketamine abuse induces cystitis in rats by impairing the bladder epithelial barrier. Mol Biol Rep 41, 7313–7322 (2014). https://doi.org/10.1007/s11033-014-3616-5

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  • DOI: https://doi.org/10.1007/s11033-014-3616-5

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