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URB 937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E 2 ‐induced bladder overactivity and hyperactivity of bladder mechano‐afferent nerve fibres in rats
Author(s) -
Aizawa Naoki,
Gandaglia Giorgio,
Hedlund Petter,
Fujimura Tetsuya,
Fukuhara Hiroshi,
Montorsi Francesco,
Homma Yukio,
Igawa Yasuhiko
Publication year - 2016
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/bju.13223
Subject(s) - fatty acid amide hydrolase , chemistry , cystometry , prostaglandin e2 , cannabinoid , dorsal root ganglion , endocrinology , prostaglandin , endocannabinoid system , urinary bladder , medicine , cannabinoid receptor , antagonist , anatomy , receptor , biochemistry , dorsum
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 E 2 ( PGE 2 ) instillation in rats. Materials and methods In female Sprague–Dawley rats we studied the effects of URB 937, a peripherally restricted FAAH inhibitor, on single‐unit afferent activity ( SAA ) during PGE 2 ‐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 PGE 2 (50 or 100 μ m ) after intravenous administration of URB 937 (0.1 and 1 mg/kg) or vehicle. In separate experiments, the comparative expressions of FAAH and cannabinoid receptors, CB 1 and CB 2 , in microsurgically removed L6 dorsal root ganglion ( DRG ) were studied by immunofluorescence. Results During CMG , 1 mg/kg URB 937, but not vehicle or 0.1 mg/kg URB 937, counteracted the PGE 2 ‐induced changes in urodynamic variables. PGE 2 increased the SAA s of C‐fibres, but not Aδ‐fibres. URB 937 (1 mg/kg) depressed Aδ‐fibre SAA and abolished the facilitated C‐fibre SAA induced by PGE 2 . The DRG nerve cells showed strong staining for FAAH , CB 1 and CB 2 , with a mean ( sem ) of 77 (2)% and 87 (3)% of FAAH ‐positive nerve cell bodies co‐expressing CB 1 or CB 2 immunofluorescence, respectively. Conclusion The present results show that URB 937, a peripherally restricted FAAH inhibitor, reduces BO and C‐fibre hyperactivity in the rat bladder provoked by PGE 2 , suggesting an important role of the peripheral endocannabinoid system in BO and hypersensitivity.