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

Naoki Aizawa, Giorgio Gandaglia, Petter Hedlund, Tetsuya Fujimura, Hiroshi Fukuhara, Francesco Montorsi, Yukio Homma, Yasuhiko Igawa

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
JournalBJU International
DOIs
Publication statusAccepted/In press - 2015

Fingerprint

Nerve Fibers
Dinoprostone
Urinary Bladder
Unmyelinated Nerve Fibers
Myelinated Nerve Fibers
Endocannabinoids
Urodynamics
Spinal Ganglia
Fluorescent Antibody Technique
Cannabinoid Receptor CB2
Intravesical Administration
Neurons
Cannabinoid Receptor CB1
Urethane
fatty-acid amide hydrolase
URB937
Intravenous Administration
Electric Stimulation
Sprague Dawley Rats
Hypersensitivity

Keywords

  • Afferent
  • Endocannabinoids
  • Prostaglandin E<inf>2</inf>
  • Sprague-Dawley rats
  • Urinary bladder

ASJC Scopus subject areas

  • Urology

Cite this

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. / Aizawa, Naoki; Gandaglia, Giorgio; Hedlund, Petter; Fujimura, Tetsuya; Fukuhara, Hiroshi; Montorsi, Francesco; Homma, Yukio; Igawa, Yasuhiko.

In: BJU International, 2015.

Research output: Contribution to journalArticle

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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. 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.",
keywords = "Afferent, Endocannabinoids, Prostaglandin E<inf>2</inf>, Sprague-Dawley rats, Urinary bladder",
author = "Naoki Aizawa and Giorgio Gandaglia and Petter Hedlund and Tetsuya Fujimura and Hiroshi Fukuhara and Francesco Montorsi and Yukio Homma and Yasuhiko Igawa",
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language = "English",
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T1 - 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

AU - Aizawa, Naoki

AU - Gandaglia, Giorgio

AU - Hedlund, Petter

AU - Fujimura, Tetsuya

AU - Fukuhara, Hiroshi

AU - Montorsi, Francesco

AU - Homma, Yukio

AU - Igawa, Yasuhiko

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Afferent

KW - Endocannabinoids

KW - Prostaglandin E<inf>2</inf>

KW - Sprague-Dawley rats

KW - Urinary bladder

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