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Aims:

Transient receptor potential melastatin 8 (TRPM8) is proposed to be a promising therapeutic target for hypersensitive bladder disorders. We examined the effects of KPR‐2579, a novel selective TRPM8 antagonist, on body temperature and on mechanosensitive bladder single‐unit afferent activities (SAAs) provoked by intravesical acetic acid (AA) instillation in rats.

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Methods:
Female Sprague‐Dawley rats were used. Effects of cumulative intravenous (i.v.) administrations of KPR‐2579 (0.03‐1 mg/kg) on deep body temperature were investigated (N  = 18). In separate animals, effects of bolus administration of KPR‐2579 (0.03 or 0.3 mg/kg, i.v.) on bladder hyperactivity induced by intravesical instillation of 0.1% AA were investigated using cystometry (N  = 57) in a conscious free‐moving condition or urethane‐anesthetized condition, and SAA measurements (N  = 41) were performed in a urethane‐anesthetized condition.

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Results
KPR‐2579 at any doses tested did not affect body temperature. In cystometry measurements, a high dose (0.3 mg/kg) of KPR‐2579 counteracted the shortened intercontraction interval provoked by AA instillation. In SAA measurements, 48 single afferent fibers (n  = 24 in each fiber) were isolated. AA instillations significantly increased the SAAs of C fibers, but not of Aδ fibers, in the presence of KPR‐2579's vehicle and a low dose (0.03 mg/kg) of KPR‐2579. Pretreatment with a high dose (0.3 mg/kg) of KPR‐2579 significantly inhibited the AA‐induced activation of C‐fiber SAAs.

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RQ-00434739, a novel TRPM8 antagonist, inhibits prostaglandin E2-induced hyperactivity of the primary bladder afferent nerves in rats.
Aizawa N, Ohshiro H, Watanabe S, Kume H, Homma Y, Igawa Y.Life Sci. 2019 Feb 1;218:89-95. doi: 10.1016/j.lfs.2018.12.031. Epub 2018 Dec 20.PMID: 30580018

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The role of transient receptor potential ankyrin 1 (TRPA1) channel in activation of single unit mechanosensitive bladder afferent activities in the rat.
Minagawa T, Aizawa N, Igawa Y, Wyndaele JJ.Neurourol Urodyn. 2014 Jun;33(5):544-9. doi: 10.1002/nau.22449. Epub 2013 Jun 19.PMID: 23784920

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KPR-5714, a Novel Transient Receptor Potential Melastatin 8 Antagonist, Improves Overactive Bladder via Inhibition of Bladder Afferent Hyperactivity in Rats.
Nakanishi O, Fujimori Y, Aizawa N, Hayashi T, Matsuzawa A, Kobayashi JI, Hirasawa H, Mutai Y, Tanada F, Igawa Y.J Pharmacol Exp Ther. 2020 May;373(2):239-247. doi: 10.1124/jpet.119.263616. Epub 2020 Feb 26.PMID: 32102918

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KPR‐2579, a novel TRPM8 antagonist, inhibits acetic acid‐induced bladder afferent hyperactivity in rats.Naoki Aizawa,Yoshikazu Fujimori,Jun‐ichi,Kobayashi,Osamu,Nakanishi,Hideaki Hirasawa ,Haruki Kume,Yukio Homma,Yasuhiko Igawa;21 February 2018 https://doi.org/10.1002/nau.23532Citations: 6.

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