Efficacy of the combination of KPR-5714, a novel transient receptor potential melastatin 8 (TRPM8) antagonist, and β3-adrenoceptor agonist or anticholinergic agent on bladder dysfunction in rats with bladder overactivity

Aizawa, Naoki; Fujimori, Yoshikazu; Nakanishi, Osamu; Hayashi, T.; Goi, Yoshiaki; Kobayashi, Jun’ichi; Fujita, Tomoe

doi:10.1016/j.ejphar.2021.173995

Cited by 13 publications

(16 citation statements)

References 33 publications

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“…KPR-5714 inhibited the exaggerated activity of mechanosensitive bladder C-fibers, increased the mean voided volume, and decreased voiding frequency, suggesting a possible alternative treatment for hyperactive bladder disorders. Aizawa et al published the effects of KPR-5714 on rhythmic bladder contractions (RBCs) in normal anesthetized rats in combination with a β3-adrenoceptor agonist or an anticholinergic agent [151]. This study first confirmed that KPR-5714 did not act on the rat β3-adrenoreceptor and M3 receptors.…”

Section: Trpm8 Antagonistsmentioning

confidence: 59%

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Izquierdo

Martı́n-Martı́nez

Gómez-Monterrey

et al. 2021

IJMS

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The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.

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Section: Trpm8 Antagonistsmentioning

confidence: 59%

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Izquierdo

Martı́n-Martı́nez

Gómez-Monterrey

et al. 2021

IJMS

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“…Additionally, it was recently demonstrated that TRPM8 channels affect chemical (acetic acid or prostaglandin E 2 )-induced pathological activation of mechanosensitive bladder C-fibers in rats ( 50 , 51 , 52 ). Moreover, the possible contribution of TRPM8 channels has also been proposed in each pathophysiological condition, such as OAB ( 52 , 53 ) and BOO in rats ( 54 , 55 ), and IC/BPS in humans ( 27 , 56 ).…”

Section: Physiological and Pathophysiological Contribution Of Trpm8 C...mentioning

confidence: 99%

“…Our previous studies suggest that TRPM8 channels contribute to activating bladder afferent pathways through mechanosensitive C-fibers ( 49 , 50 , 51 , 52 ), and this specific mechanism of the TRPM8 channel on sensory bladder function may possibly contribute to the storage symptoms, such as urinary urgency in OAB. Additionally, it was recently revealed that the combined administration of KPR-5714 and mirabegron (a β 3 -adrenoceptor agonist) or tolterodine tartrate (an anticholinergic agent) indicated the additive effects on bladder overactivity caused by cold exposure and cerebral infarction in rats, suggesting that the combination therapy using an TRPM8 antagonist with a β 3 -adrenoceptor agonist or anticholinergic agent can be the potential treatment option for obtaining an additive effect compared with the monotherapy for OAB ( 53 ).…”

Section: Trpm8 Channel Related To Oabmentioning

confidence: 99%

The TRPM8 channel as a potential therapeutic target for bladder hypersensitive disorders

Aizawa

Fujita

2022

J. Smooth Muscle Res.

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In the lower urinary tract, transient receptor potential (TRP) channels are primarily involved in physiological function, especially in cellular sensors responding to chemical and physical stimuli. Among TRP channels, TRP melastatin 8 (TRPM8) channels, responding to cold temperature and/or chemical agents, such as menthol or icilin, are mainly expressed in the nerve endings of the primary afferent neurons and in the cell bodies of dorsal root ganglia innervating the urinary bladder (via Aδ- and C-fibers); this suggests that TRPM8 channels primarily contribute to bladder sensory (afferent) function. Storage symptoms of overactive bladder, benign prostatic hyperplasia, and interstitial cystitis are commonly related to sensory function (bladder hypersensitivity); thus, TRPM8 channels may also contribute to the pathophysiology of bladder hypersensitivity. Indeed, it has been reported in a pharmacological investigation using rodents that TRPM8 channels contribute to the pathophysiological bladder afferent hypersensitivity of mechanosensitive C-fibers. Similar findings have also been reported in humans. Therefore, a TRPM8 antagonist would be a promising therapeutic target for bladder hypersensitive disorders, including urinary urgency or nociceptive pain. In this review article, the functional role of the TRPM8 channel in the lower urinary tract and the potential of its antagonist for the treatment of bladder disorders was described.

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“…combined with β3-adrenoceptor agonist or anticholinergic agent on rats with OAB, demonstrating that the combined administration of KPR-5714 and mirabegron or tolterodine tartrate additively reduced bladder contractions and voiding frequency, in comparison with monotherapy. 107 O-1602 is a novel agonist of GPR55 and GPR18 cannabinoid receptors which are expressed in the bladder and involved in the peripheral modulation of bladder afferent information. 108 Several clinical trials have indicated that oral agents which modulate cannabinoid receptor activity might be an alternative therapy for patients with OAB.…”

Section: New Agentsmentioning

confidence: 99%

“…Aizawa et al investigated the effects of TRPM8 antagonist combined with β3-adrenoceptor agonist or anticholinergic agent on rats with OAB, demonstrating that the combined administration of KPR-5714 and mirabegron or tolterodine tartrate additively reduced bladder contractions and voiding frequency, in comparison with monotherapy. 107 …”

Section: New Agentsmentioning

confidence: 99%