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

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

 

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.

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

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.

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

 

 

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