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

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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

 

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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.

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

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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.

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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

 

1 Aizawa N, Gandaglia G, Hedlund P et al. 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. BJU Int 2016; 117: 821–8

 

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: 9371–6

 

3 Maccarrone M, Bab I, Bıro T et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 2015; 36: 277–96

 

4 Hedlund P. Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. Neurourol Urodyn 2014; 33: 46–53

 

5 Birder L, Andersson KE. Urothelial signaling. Physiol Rev 2013; 93: 653–80

 

6 Wang ZY, Wang P, Bjorling DE. Activation of cannabinoid receptor 1 inhibits increased bladder activity induced by nerve growth factor. Neurosci Lett 2015; 589: 19–24

 

Article of the Week: Functional role of the TRPM8 ion channel in the bladder

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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.

Functional role of the transient receptor potential melastatin 8 (TRPM8) ion channel in the urinary bladder assessed by conscious cystometry and ex vivo measurements of single-unit mechanosensitive bladder afferent activities in the rat

 

Hiroki Ito*†, Naoki Aizawa*, Rino Sugiyama*‡, Shuzo Watanabe§, Nobuyuki Takahashi§, Masaomi Tajimi§, Hiroshi Fukuhara‡, Yukio Homma‡, Yoshinobu Kubota†, Karl-Erik Andersson¶ and Yasuhiko Igawa*

 

Departments of *Continence Medicine, ‡Urology, The University of Tokyo Graduate School of Medicine, Tokyo, †Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, §RaQualia Pharma Inc., Nagoya, Japan, and Aarhus Institute of Advanced Studies, Aarhus University, Aarhus, Denmark

 

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Objective

To evaluate the role of the transient receptor potential melastatin 8 (TRPM8) channel on bladder mechanosensory function by using L-menthol, a TRPM8 agonist, and RQ-00203078 (RQ), a selective TRPM8 antagonist.

Materials and methods

Female Sprague–Dawley rats were used. In conscious cystometry (CMG), the effects of intravesical instillation of L-menthol (3 mm) were recorded after intravenous (i.v.) pretreatment with RQ (3 mg/kg) or vehicle. The direct effects of RQ on conscious CMG and deep body temperature were evaluated with cumulative i.v. administrations of RQ at 0.3, 1, and 3 mg/kg. Single-unit mechanosensitive bladder afferent activities (SAAs) were monitored in a newly established ex vivo rat bladder model to avoid systemic influences of the drugs. Recordings were performed after cumulative intra-aortic administration of RQ (0.3 and 3 mg/kg) with or without intra-vesical L-menthol instillation (3 mm).

Mar AOTW2

Results

Intravesical L-menthol decreased bladder capacity and voided volume, which was counteracted by RQ-pretreatment. RQ itself increased bladder capacity and voided volume, and lowered deep body temperature in a dose-dependent manner. RQ decreased mechanosensitive SAAs of C-fibres, and inhibited the activation of SAAs induced by intravesical L-menthol.

Conclusion

Our results suggest that TRPM8 channels have a role in activation of bladder afferent pathways during filling of the bladder in the normal rat. This effect seems, at least partly, to be mediated via mechanosensitive C-fibres.

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Editorial: TRPM8 antagonists to treat LUTS- don’t lose your cool just yet

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The sensory mechanisms of the lower urinary tract enable our brain to continuously monitor the filling status of the bladder. During urine storage, low-level afferent information is mostly processed subconsciously. As the bladder fills up with urine, afferent signalling increases until we start feeling the urge to pass urine and we can consciously initiate voiding Under pathological conditions, such as urinary tract infection, overactive bladder or painful bladder syndrome, the afferent mechanisms become sensitized and lead to mechanical hypersensitivity, which is responsible for symptoms as urinary urgency, frequency and even pain.

In the current issue of BJUI, Ito et al. [1] describe the role of the ion channel transient receptor potential subtype melastatin 8 (TRPM8) in mechanosensation in the bladder (detection of the bladder’s filling status). By performing continuous cystometry in freely moving rats, they show that activation of TRPM8 decreases the threshold for initiation of micturition. I.v. administration of the TRPM8 antagonist RQ-00203078 significantly increased bladder capacity and voided volume. This antagonist also prevented the facilitating effects of intravesical L-Menthol, a TRPM8 agonist on the voiding reflex. Moreover in a specialized ex vivo rat model created to study the activity of mechanosensory fibres, pharmacological blockade of TRPM8 by RQ-00203078 inhibited single-unit mechanosensitive bladder afferent activity (SAA) during bladder filling. Conversely, L-Menthol facilitated SAA in a TRPM8-dependent manner. This indicates that TRPM8 activity directly influences the sensory information that is generated by mechanosensory neurons during urine accumulation.

TRPM8 is expressed in a subpopulation of dorsal root ganglion neurons that innervate the skin and the visceral organs, including the urinary bladder. Its activity can be increased by cold temperatures (<28 °C) and cooling chemicals, such as menthol and icilin; however, TRPM8 does not respond to mechanical stimuli in heterologous expression systems, suggesting that TRPM8 affects the excitability of mechanosensory neurons rather than acts as a mechanosensor itself [2].

Two recent publications have also highlighted the importance of TRPM8 in bladder hypersensitivity disorders. Uvin et al. [3] reported the pivotal role of TRPM8 in acute cold-induced urgency. Using rats and mice, they showed that exposure of part of the skin to innocuous cold evokes bladder contractions and reflex voiding in a TRPM8-dependent manner. Their findings provide a physiological basis for the worsening of storage symptoms in response to environmental cold stimuli, as a result of activation of TRPM8. Using the oral TRPM8 antagonist PF-05105679, Winchester et al. [4] described TRPM8 as the essential cold sensor in the bladder cooling reflex in guinea pigs. Importantly, this group also conducted a phase I clinical trial using this antagonist. In their trial, PF-05105679 successfully blocked cold-induced pain in healthy volunteers who were exposed to the cold pressor test.

Altogether these data strongly support the therapeutic potential of TRPM8 modulators to treat bladder hypersensitivity disorders. Unfortunately, because of the widespread expression of these channels and their role in various homeostatic and sensory processes, pharmacological inhibition of TRP channels often leads to side effects that limit their clinical use [5]. In preclinical models, inhibition of TRPM8 leads to transient hypothermia, which was confirmed by Ito et al. [1]. They observed a dose-dependent decrease in deep body temperature after i.v. administration of RQ-00203078. In the only published clinical trial so far, PF-05105679 did not induce hypothermia but evoked a dose-dependent peri-oral burning sensation. This unexpected side effect limits the further clinical development of PF-05105679 and potentially of all TRPM8 antagonists.

In conclusion, our increasing knowledge about the functional role of TRPM8 in the urinary bladder is important to better understand the pathophysiology of functional bladder disorders, but does not yet offer an adequate therapeutic solution.

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Wouter Everaerts, *,† and Dirk De Ridder, *,†

 

*Department of Development and Regeneration, Urology, KU Leuven, and †TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium

 

References

 

1 Ito H, Aizawa N, Sugiyama R et al. Functional role of the transient receptor potential melastatin 8 (TRPM8) ion channel in the urinary bladder assessed by conscious cystometry and ex vivo measurements of single-unit mechanosensitive bladder afferent activities in the rat. BJU Int 2016; 117: 484–94

 

2 Kaneko Y, Szallasi A. Transient receptor potential (TRP) channels: a clinical perspective. Br J Pharmacol 2014; 171: 2474–507

 

3 Uvin P, Franken J, Pinto S et al. Essential role of Transient Receptor Potential M8 (TRPM8) in a model of acute cold-induced urinary urgency. Eur Urol 2015; 68: 655–61

 

4 Winchester WJ, Gore K, Glatt S et al. Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans. J Pharmacol Exp Ther 2014; 351: 259–69

 

5 Deruyver Y, Voets T, De Ridder D, Everaerts W. Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality? BJU Int 2015; 115: 686–97

 

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