KPR‐2579, a novel TRPM8 antagonist, inhibits acetic acid‐induced bladder afferent hyperactivity in rats

Aizawa, Naoki; Fujimori, Yoshikazu; Kobayashi, Jun’ichi; Nakanishi, Osamu; Hirasawa, H.; Kume, Haruki; Homma, Yukio; Igawa, Yasuhiko

doi:10.1002/nau.23532

Cited by 25 publications

(32 citation statements)

References 24 publications

(53 reference statements)

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“…The difference in columnar activation could be explained by the stimulation of different types of afferent fibers. Indeed, in the case of acetic acid infusion, mainly unmyelinated c-fibers respond to noxious stimuli (Aizawa et al, 2018 ). Electrically evoked (sub-micturition threshold) contractions generated increased activity through central pathways that control the urinary bladder, initiated by activation of sensory axons.…”

Section: Discussionmentioning

confidence: 99%

Neuronal Activation in the Periaqueductal Gray Matter Upon Electrical Stimulation of the Bladder

Meriaux

Hohnen

Schipper

et al. 2018

Front. Cell. Neurosci.

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Reflexes, that involve the spinobulbospinal pathway control both storage and voiding of urine. The periaqueductal gray matter (PAG), a pontine structure is part of the micturition pathway. Alteration in this pathway could lead to micturition disorders and urinary incontinence, such as the overactive bladder symptom complex (OABS). Although different therapeutic options exist for the management of OABS, these are either not effective in all patients. Part of the pathology of OABS is faulty sensory signaling about the filling status of the urinary bladder, which results in aberrant efferent signaling leading to overt detrusor contractions and the sensation of urgency and frequent voiding. In order to identify novel targets for therapy (i.e., structures in the central nervous system) and explore novel treatment modalities such as neuromodulation, we aimed at investigating which areas in the central nervous system are functionally activated upon sensory afferent stimulation of the bladder. Hence, we designed a robust protocol with multiple readout parameters including immunohistological and behavioral parameters during electrical stimulation of the rat urinary bladder. Bladder stimulation induced by electrical stimulation, below the voiding threshold, influences neural activity in: (1) the caudal ventrolateral PAG, close to the aqueduct; (2) the pontine micturition center and locus coeruleus; and (3) the superficial layers of the dorsal horn, sacral parasympathetic nucleus and central canal region of the spinal cord. In stimulated animals, a higher voiding frequency was observed but was not accompanied by increase in anxiety level and locomotor deficits. Taken together, this work establishes a critical role for the vlPAG in the processing of sensory information from the urinary bladder and urges future studies to investigate the potential of neuromodulatory approaches for urological diseases.

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Section: Discussionmentioning

confidence: 99%

Neuronal Activation in the Periaqueductal Gray Matter Upon Electrical Stimulation of the Bladder

Meriaux

Hohnen

Schipper

et al. 2018

Front. Cell. Neurosci.

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“…Kashyap et al observed the overexpression of nerve growth factor and inflammatory molecules in an OAB model induced by intravesical AA instillation (0.25%) in rats,27 while Aizawa et al recently reported that a transient receptor potential melastatin 8 antagonist inhibited afferent overactivity induced by intravesical AA instillation (0.1%) 28. Transient receptor potential melastatin 8 channels are expressed in urothelial cells, sensory nerve fibers within the urothelium and suburothelium of the bladder, and the L6 dorsal root ganglia of rats and guinea pigs 29,30.…”

mentioning

confidence: 99%

Therapeutic effects of Choreito, a traditional Japanese (Kampo) medicine, on detrusor overactivity induced by acetic acid in rats

Ueno

Minagawa

Saito

et al. 2020

LUTS

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Choreito (CRT), a traditional Japanese (Kampo) medicine, is widely used for the treatment of overactive bladder (OAB) and other lower urinary tract symptoms in Japan. This study aimed to identify the effects and therapeutic mechanism of CRT on the improvement of detrusor overactivity (DO) using an experimental rat model. Forty‐five female Sprague‐Dawley rats were equally divided into three groups: intravesical saline instillation with normal food (normal group), intravesical acetic acid (AA) instillation with normal food (AA group), and intravesical AA instillation with CRT (AA with CRT group). To induce a decrease in bladder capacity, instillation of 0.2% AA was used based on prior studies. Cystometric investigation was employed to clarify the effects of AA and CRT. Microcirculation was performed using a laser blood flowmeter, and the localization of hypoxia‐inducible factor 1α (HIF1α) was assessed by immunohistochemistry. The bladder capacities of the normal, AA, and AA with CRT groups were 1.2 ± 0.3 mL, 0.4 ± 0.1 mL, and 0.8 ± 0.1 mL, respectively. CRT significantly attenuated AA irritation of the urinary bladder and exerted protective effects on basal pressure, micturition pressure, micturition interval, and micturition volume. Furthermore, CRT could prevent the excess blood flow and edematous change under the urothelium induced by intravesical AA instillation. No obvious changes in immunohistochemical HIF1α staining were observed among the groups. CRT attenuated DO induced by intravesical AA instillation in a rat experimental model. CRT might impart therapeutic effects on OAB via the mitigation of urothelial damage and regulation of excess blood flow.

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“…Both distention of the bladder and painful stimuli may activate the PAG, with different patterns. The vlPAG, among other regions, was activated in human PET scans after bladder distension, but not with intravesical ice bladder instillation, revealing different pathways in bladder distension and pain [78]. fMRI on healthy females shows that cold (pain) sensation is processed differently from bladder distension at the supraspinal level [79].…”

Section: Functional Imaging Of the Pagmentioning

confidence: 92%

“…The difference in columnar activation could be explained by the stimulation of different types of afferent fibers. Indeed, in the case of acetic acid infusion, mainly unmyelinated c-fibers respond to noxious stimuli [78]. Electrically evoked (submicturition threshold) contractions generated increased activity through central pathways that control the urinary bladder, initiated by activation of sensory axons.…”

Section: Neuronal Activation Of the Pag By Electrical Stimulationmentioning

confidence: 99%

Unveiling the sensory connections between the bladder and the brain that involve the periaqueductal gray matter

Zare¹

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KPR‐2579, a novel TRPM8 antagonist, inhibits acetic acid‐induced bladder afferent hyperactivity in rats

Abstract: The present results suggest that TRPM8 channels play a role in the AA-induced pathological activation of mechanosensitive bladder C fibers in rats. KRP-2579 may be a promising drug for hypersensitive bladder disorders.

Cited by 25 publications

References 24 publications

Neuronal Activation in the Periaqueductal Gray Matter Upon Electrical Stimulation of the Bladder

Neuronal Activation in the Periaqueductal Gray Matter Upon Electrical Stimulation of the Bladder

Therapeutic effects of Choreito, a traditional Japanese (Kampo) medicine, on detrusor overactivity induced by acetic acid in rats

Unveiling the sensory connections between the bladder and the brain that involve the periaqueductal gray matter

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