title: Long-term ketamine abuse induces cystitis in rats by impairing the bladder epithelial barrier.
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.
authors.affiliation: Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
authors.forename: Di
authors.initials: D
authors.lastname: Gu
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.forename: Youle
authors.initials: Y
authors.lastname: Yin
authors.forename: Zhengfei
authors.initials: Z
authors.lastname: Shan
authors.forename: Shaobin
authors.initials: S
authors.lastname: Zheng
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine; D015153:Blotting, Western; D003556:Cystitis / Q000139:chemically induced* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects*; D006652:Histological Techniques; D007150:Immunohistochemistry; D007649:Ketamine / Q000008:administration & dosage / Q000009:adverse effects* / Q000652:urine; D051381:Rats; D019966:Substance-Related Disorders / Q000378:metabolism*; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects*; D014556:Urine
chemical_list: D015415:Biomarkers; D007649:Ketamine
references.citation: Urology. 2001 Jun;57(6 Suppl 1):9-14
references.pmid: 11378043
references.citation: Int J Cell Biol. 2012;2012:150918
references.pmid: 22536245
references.citation: J Urol. 2001 Apr;165(4):1342-6
references.pmid: 11257713
references.citation: J Exp Clin Cancer Res. 2010 Dec 10;29:160
references.pmid: 21143984
references.citation: Shock. 2002 Feb;17(2):139-45
references.pmid: 11837790
references.citation: Curr Opin Anaesthesiol. 2010 Aug;23(4):455-60
references.pmid: 20531172
references.citation: Urology. 2007 Apr;69(4 Suppl):34-40
references.pmid: 17462477
references.citation: J Urol. 2008 May;179(5):1850-6
references.pmid: 18353383
references.citation: J Urol. 1996 Dec;156(6):2073-8
references.pmid: 8911393
references.citation: J Urol. 1990 Apr;143(4):690-3
references.pmid: 2313793
references.citation: J Urol. 2004 Apr;171(4):1554-8
references.pmid: 15017219
references.citation: Toxicol Lett. 2009 Dec 15;191(2-3):275-8
references.pmid: 19766175
references.citation: Fa Yi Xue Za Zhi. 2010 Oct;26(5):357-60
references.pmid: 21287740
references.citation: Microsc Res Tech. 2011 Dec;74(12):1192-8
references.pmid: 21563274
references.citation: Urol Int. 2012;89(1):93-6
references.pmid: 22710265
references.citation: BJU Int. 2011 Feb;107(3):370-5
references.pmid: 21176078
references.citation: BMC Urol. 2012 Jun 08;12:17
references.pmid: 22682521
references.citation: Cell Signal. 2008 Dec;20(12):2174-9
references.pmid: 18602988
references.citation: Urol Clin North Am. 1994 Feb;21(1):21-30
references.pmid: 8284842
references.citation: Urology. 2001 Jun;57(6 Suppl 1):15-21
references.pmid: 11378044
references.citation: Int J Urol. 2011 Oct;18(10):735
references.pmid: 21848631
references.citation: J Urol. 2005 Apr;173(4):1182-5
references.pmid: 15758737
references.citation: J Urol. 1990 Jan;143(1):139-42
references.pmid: 1688456
references.citation: J Urol. 1999 Jun;161(6):1786-90
references.pmid: 10332435
references.citation: BJU Int. 2008 Dec;102(11):1616-22
references.pmid: 18680495
references.citation: BJU Int. 2011 Jun;107(12):1881-4
references.pmid: 21314885
references.citation: J Urol. 2005 Feb;173(2):625-9
references.pmid: 15643277
references.citation: Urology. 1996 Nov;48(5):700-2
references.pmid: 8911512
references.citation: Hong Kong Med J. 2007 Aug;13(4):311-3
references.pmid: 17592176
references.citation: Nat Rev Mol Cell Biol. 2003 Mar;4(3):225-36
references.pmid: 12612641
references.citation: J Urol. 2000 Oct;164(4):1381-4
references.pmid: 10992419
references.citation: J Urol. 2005 Dec;174(6):2382-7
references.pmid: 16280852
references.citation: J Anal Toxicol. 2005 Jul-Aug;29(5):376-82
references.pmid: 16105264