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Article of the Week: URB937 reduces PGE2-induced bladder overactivity

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

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¶ and Yasuhiko Igawa*

 

Departments of *Continence Medicine, Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan, Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy, Department of Clinical and Experimental Pharmacology, Lund University, Lund, and §Division of Drug Research, Department of Medical and Health Sciences, Linkoping University, Linkoping, Sweden

 

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.

May AOTW 2 resutls

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.

Editorial: Unmasking roles of the peripheral endocannabinoid system associated with bladder overactivity

Identifying regulatory roles of peripheral endocannabinoid systems for bladder function is a highly intricate task; nonetheless, in this issue of BJUI, a research report by Aizawa et al. [1] shows functional evidence for a role of fatty acid amide hydrolase (FAAH) in improving bladder overactivity induced by prostaglandin E2 (PGE2) in rats. By systemically blocking FAAH with URB937, an inhibitor of FAAH that does not penetrate the CNS, the authors found that afferent nerve activity and bladder cystometric parameters decreased in a rat overactive bladder model induced by intravesical perfusion of PGE2. Confirmation that ≈80% of dorsal root neurones at the Lumbar-6 dorsal root ganglia co-express FAAH and cannabinoid receptors 1 and 2 (CB1, CB2), emphasises the role of the peripheral endocannabinoid system during bladder overactivity induced by increased activity of C-fibres during PGE2 application.

Because FAAH catabolises CB ligands rapidly, a key regulatory role for pain perception was initially proposed [2]. Now, we recognise that the peripheral endocannabinoid system participates in both normal physiology and pathological conditions of the heart, liver, immune system, bone, skin, skeletal muscle, reproduction, and gastrointestinal tract [3]. The participation of the endocannabinoid system in regulating lower urinary tract function has been less studied; however, research evidence suggest an important regulatory role at different levels of the micturition reflex [4]. The study of Aizawa et al. [1] is important because it shows that the rat urinary bladder can be affected by the catabolism of endogenous ligands for CB1 and CB2 during systemic FAAH inhibition in conditions of bladder overactivity induced by PGE2. However, the experiments were performed in conditions where the urothelial cell layer was disturbed with the intravesical application of protamine sulphate. Although this seems to be the best approach to induce bladder overactivity with PGE2, it disturbs the sensory role of the urothelium for monitoring the urinary bladder filling status [5]. Thus, an alternative model for bladder overactivity requires an evaluation of an FAAH inhibitor. Supporting this suggestion, a recent report by Wang et al. [6] shows that intravesical application of a CB1agonist decreases bladder overactivity induced by intravesical nerve growth factor (NGF) in mice with an intact urothelial layer. Additionally, NGF did not induce bladder overactivity in knockout mice for the FAAH enzyme, reinforcing the suggestion for Aizawa et al. [1] about testing the peripherally-restricted inhibition of FAAH with URB937 in urothelium-intact rats.

The above comments and references recommend the performance of a pre-clinical evaluation of the endocannabinoid system using FAAH inhibitors to treat, for instance, neurogenic bladder overactivity in rats with spinal cord injury. Naturally, this overactive bladder model will prove to be more complicated and challenging to evaluate, but the results may provide overwhelming support for a rigorous assessment of the use of cannabinoids to treat urinary bladder dysfunction in humans [3]. At the mechanistic level it would be interesting to know at what part(s) of the micturition reflex is FAAH regulating bladder function. How significant is the catabolism of endogenous CB1/CB2 receptors during the storage and contraction phases of either normal or altered micturition? While the current study of Aizawa et al. [1] contributes to a deeper knowledge of the cannabinoid system in bladder dysfunction, additional studies are required to determine whether systemic inhibition of FAAH improves C-fibre mediated bladder sensory pathways in other animal models of detrusor and bladder overactivity.

Alvaro Munoz, Assistant Research Professor of Urology
Departments of Regenerative Medicine and Urology, Houston Methodist Research Institut e and Houston Methodist Hospital, Houston, TX, USA

 

References

 

 

2 Cravatt BF, Demarest K, Patricelli MP et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 2001; 98: 93716

 

3 Maccarrone M, Bab I, Bıro T et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 2015; 36: 27796

 

 

5 Birder L, Andersson KE. Urothelial signaling. Physiol Rev 2013; 93: 65380

 

 

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