title: URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E2 -induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres in rats.
abstract: OBJECTIVE
  To determine if inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) can counteract the changes in urodynamic variables and bladder afferent activities induced by intravesical prostaglandin E2 (PGE2 ) instillation in rats.
  
  
  METHODS
  In female Sprague-Dawley rats we studied the effects of URB937, a peripherally restricted FAAH inhibitor, on single-unit afferent activity (SAA) during PGE2 -induced bladder overactivity (BO). SAA measurements were made in urethane-anaesthetised rats and Aδ- and C-fibres were identified by electrical stimulation of the pelvic nerve and by bladder distention. Cystometry (CMG) in conscious animals and during SAA measurements was performed during intravesical instillation of PGE2 (50 or 100 μm) after intravenous administration of URB937 (0.1 and 1 mg/kg) or vehicle. In separate experiments, the comparative expressions of FAAH and cannabinoid receptors, CB1 and CB2 , in microsurgically removed L6 dorsal root ganglion (DRG) were studied by immunofluorescence.
  
  
  RESULTS
  During CMG, 1 mg/kg URB937, but not vehicle or 0.1 mg/kg URB937, counteracted the PGE2 -induced changes in urodynamic variables. PGE2 increased the SAAs of C-fibres, but not Aδ-fibres. URB937 (1 mg/kg) depressed Aδ-fibre SAA and abolished the facilitated C-fibre SAA induced by PGE2 . The DRG nerve cells showed strong staining for FAAH, CB1 and CB2 , with a mean (sem) of 77 (2)% and 87 (3)% of FAAH-positive nerve cell bodies co-expressing CB1 or CB2 immunofluorescence, respectively.
  
  
  CONCLUSIONS
  The present results show that URB937, a peripherally restricted FAAH inhibitor, reduces BO and C-fibre hyperactivity in the rat bladder provoked by PGE2 , suggesting an important role of the peripheral endocannabinoid system in BO and hypersensitivity.
authors.affiliation: Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Aizawa
authors.affiliation: Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.|Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gandaglia
authors.affiliation: Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Hedlund
authors.affiliation: Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukuhara
authors.affiliation: Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Montorsi
authors.affiliation: Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.affiliation: Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Igawa
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone; D005260:Female; D007150:Immunohistochemistry; D008465:Mechanoreceptors / Q000187:drug effects* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation*; D053201:Urinary Bladder, Overactive / Q000139:chemically induced / Q000188:drug therapy*; D014563:Urodynamics / Q000187:drug effects; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D002186:Cannabinoids; D015232:Dinoprostone; D000099252:Fatty Acid Amide Hydrolases; C552918:URB937
keywords: Afferent; Sprague-Dawley rats; endocannabinoids; prostaglandin E2; urinary bladder