title: Protamine sulfate induced bladder injury protects from distention induced bladder pain.
abstract: OBJECTIVE
  Bladder pain is a debilitating symptom of many urological conditions. There is no generally effective treatment. Abnormal urothelial turnover is common to multiple disease states but the specific components of urothelial injury and the resulting molecular signals that lead to bladder pain are unknown. We examined mouse models of bladder injury induced by uropathogenic Escherichia coli, protamine sulfate (Sigma®) and bacterial lipopolysaccharide to identify cellular and molecular correlates underlying pain sensitization in response to the stimuli.
  
  
  METHODS
  C57BL/6 female mice (Jackson Laboratory, Bar Harbor, Maine) were given intravesicular protamine sulfate, lipopolysaccharide or uropathogenic E. coli. The impact of each on nociception was determined by measuring the evoked visceromotor response to bladder distention 24 hours after inoculation. Levels of pyuria and tissue inflammation were examined by urinary cytology and tissue histology. Quantitative polymerase chain reaction and gene expression analysis were used to identify injury profiles associated with nociception.
  
  
  RESULTS
  Protamine sulfate treatment was significantly analgesic upon bladder distention. Protamine treated bladders did not show pyuria or extensive tissue damage. Protamine injury was associated with a global decrease in the expression of inflammation associated genes. In contrast, uropathogenic E. coli injury significantly increased the nociceptive response to bladder distention. Lipopolysaccharide treatment did not affect nociception. Finally, injury induced expression of inflammation associated genes correlated with nociceptive responses.
  
  
  CONCLUSIONS
  Protamine treatment of the bladder is analgesic and tissue protective, and it suppresses the inflammatory cytokine expression normally associated with nociception. Also, the injury modalities that result in differential tissue response patterns provide an innovative method for identifying mediators of visceral pain.
authors.affiliation: Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Stemler
authors.forename: Lara W
authors.initials: LW
authors.lastname: Crock
authors.forename: H Henry
authors.initials: HH
authors.lastname: Lai
authors.forename: Jason C
authors.initials: JC
authors.lastname: Mills
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gereau
authors.forename: Indira U
authors.initials: IU
authors.lastname: Mysorekar
mesh_terms: D000818:Animals; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D011479:Protamines / Q000008:administration & dosage / Q000627:therapeutic use*; D001743:Urinary Bladder; D001745:Urinary Bladder Diseases / Q000139:chemically induced; D059265:Visceral Pain / Q000517:prevention & control*
chemical_list: D011479:Protamines