Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction

Am J Physiol Renal Physiol. 2016 May 1;310(9):F885-94. doi: 10.1152/ajprenal.00483.2015. Epub 2016 Feb 24.


Ketamine is a popular choice for young drug abusers. Ketamine abuse causes lower urinary tract symptoms, with the underlying pathophysiology poorly understood. Disruption of urothelial barrier function has been hypothesized to be a major mechanism for ketamine cystitis, yet the direct evidence of impaired urothelial barrier function is still lacking. To address this question, 8-wk-old female C57BL/6J mice were injected intraperitoneally with 30 mg·kg(-1)·day(-1) ketamine for 12 wk to induce ketamine cystitis. A spontaneous voiding spot assay showed that ketamine-treated mice had increased primary voiding spot numbers and smaller primary voiding spot sizes than control mice (P < 0.05), indicating a contracted bladder and bladder overactivity. Consistently, significantly increased voiding frequency was observed in ketamine-treated mice on cystometrograms. These functional experiments indicate that ketamine induces voiding dysfunction in mice. Surprisingly, urothelial permeability in ketamine-treated mice was not changed when measured using an Ussing chamber system with isotopic urea and water. Mouse urothelial structure was also not altered, and intact umbrella cell structure was observed by both transmission and scanning electron microscopy. Furthermore, immunostaining and confocal microscopy confirmed the presence of a well-defined distribution of zonula occuldens-1 in tight junctions and uroplakin in umbrella cells. In conclusion, these data indicate that ketamine injection induces voiding dysfunction in mice but does not necessarily disrupt mouse bladder barrier function. Disruption of urothelial barrier function may not be the major mechanism in ketamine cystitis.

Keywords: ketamine cystitis; permeability; umbrella cell; urinary bladder; voiding spot assay.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthetics, Dissociative
  • Animals
  • Cystitis / chemically induced*
  • Cystitis / pathology*
  • Female
  • Ketamine
  • Mice
  • Mice, Inbred C57BL
  • Permeability
  • Tight Junction Proteins / metabolism
  • Urinary Bladder / physiopathology
  • Urinary Bladder, Overactive / chemically induced
  • Urinary Bladder, Overactive / physiopathology
  • Urothelium / pathology*
  • Urothelium / ultrastructure
  • Zonula Occludens-1 Protein / metabolism


  • Anesthetics, Dissociative
  • Tight Junction Proteins
  • Zonula Occludens-1 Protein
  • Ketamine