title: The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats.
abstract: OBJECTIVE
  To study micturition and bladder overactivity in female rats after chronic treatment with the fatty acid amide hydrolase (FAAH) inhibitor oleoyl ethyl amide (OEtA).
  
  
  METHODS
  Sprague-Dawley rats received daily subcutaneous injections of OEtA (0.3 mg/kg), or vehicle for 2 weeks. Cystometries, organ bath studies, Western blot, and immunofluorescence were then used. Expressions of FAAH, cannabinoid 1 and 2 receptors (CB1 and CB2), mitogen-activated protein kinase (MAPK), vesicular acetyl choline-transporter protein (VAChT), and calcitonin gene-related peptide (CGRP) were evaluated.
  
  
  RESULTS
  At baseline, OEtA-treated rats had higher values (P < 0.05) of micturition intervals (MI) and volumes (MV), bladder capacity (BC), threshold pressure, and flow pressure than vehicle controls. Intravesical PGE2 reduced MI, MV, and BC, and increased basal pressure and the area under the curve in all rats. However, these urodynamic parameters were altered less by intravesical PGE2 in OEtA-treated rats (P < 0.05 vs. vehicle controls). Compared to vehicle controls, detrusor from OEtA-treated rats had larger contractions to carbachol at 10-0.1 µM, but no difference in Emax was recorded. FAAH, CB1, CB2, VAChT, or CGRP was similarly expressed in bladders from all rats. In separate experiments, intravesical OEtA increased mucosal expression of phosphorylated MAPK.
  
  
  CONCLUSIONS
  Chronic FAAH inhibition altered sensory urodynamic parameters and reduced bladder overactivity. Even if it cannot be excluded that OEtA may act on central nervous sensory pathways to contribute to these effects, the presence of FAAH and CB receptors in the bladder and activation of intracellular signals for CB receptors by intravesical OEtA suggest a local role for FAAH in micturition control.
authors.affiliation: Urological Research Institute, San Raffaele Scientific Institute, Milan, Italy; Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gandaglia
authors.forename: Frank
authors.initials: F
authors.lastname: Strittmatter
authors.forename: Giovanni
authors.initials: G
authors.lastname: La Croce
authors.forename: Fabio
authors.initials: F
authors.lastname: Benigni
authors.forename: Arianna
authors.initials: A
authors.lastname: Bettiga
authors.forename: Fabio
authors.initials: F
authors.lastname: Castiglione
authors.forename: Marco
authors.initials: M
authors.lastname: Moschini
authors.forename: Francesco
authors.initials: F
authors.lastname: Mistretta
authors.forename: Christian
authors.initials: C
authors.lastname: Gratzke
authors.forename: Francesco
authors.initials: F
authors.lastname: Montorsi
authors.forename: Christian
authors.initials: C
authors.lastname: Stief
authors.forename: Petter
authors.initials: P
authors.lastname: Hedlund
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D005260:Female; D009829:Oleic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D009829:Oleic Acids; D000099252:Fatty Acid Amide Hydrolases; C571010:oleoyl ethyl amide
keywords: cannabinoid receptor; endocannabinoid system; mitogen-activated protein kinase; urinary bladder