Naoki Aizawa1, Giorgio Gandaglia2,3, Petter Hedlund4, Tetsuya Fujimura5, Hiroshi Fukuhara5, Francesco Montorsi2, Yukio Homma5, Yasuhiko Igawa1. 1. Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan. 2. Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy. 3. Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden. 4. Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden. 5. Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
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. MATERIALS AND 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. CONCLUSION: 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.
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. MATERIALS AND 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. CONCLUSION: 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: Christopher L Langdale; James A Hokanson; Philip H Milliken; Arun Sridhar; Warren M Grill Journal: Am J Physiol Renal Physiol Date: 2020-04-20