RQ-00434739, a novel TRPM8 antagonist, inhibits prostaglandin E2-induced hyperactivity of the primary bladder afferent nerves in rats

Aizawa, Naoki; Ohshiro, Hiroyuki; Watanabe, Shuzo; Kume, Haruki; Homma, Yukio; Igawa, Yasuhiko

doi:10.1016/j.lfs.2018.12.031

Cited by 17 publications

(32 citation statements)

References 28 publications

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“…Several new antagonists have been described [124,125], and some of them have been tested in animals for their effects on normal LUT and in models of LUT disorders [80,82,126,127,128,129,130].…”

Section: Trp Channel Agonists and Antagonistsmentioning

confidence: 99%

TRP Channels as Lower Urinary Tract Sensory Targets

Andersson

2019

Medical Sciences

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Several members of the transient receptor potential (TRP) superfamily, including TRPV1, TRPV2, TRPV4, TRM4, TRPM8 and TRPA1, are expressed in the lower urinary tract (LUT), not only in neuronal fibers innervating the bladder and urethra, but also in the urothelial and muscular layers of the bladder and urethral walls. In the LUT, TRP channels are mainly involved in nociception and mechanosensory transduction. Animal studies have suggested the therapeutic potential of several TRP channels for the treatment of both bladder over- and underactivity and bladder pain disorders,; however translation of this finding to clinical application has been slow and the involvement of these channels in normal human bladder function, and in various pathologic states have not been established. The development of selective TRP channel agonists and antagonists is ongoing and the use of such agents can be expected to offer new and important information concerning both normal physiological functions and possible therapeutic applications.

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Section: Trp Channel Agonists and Antagonistsmentioning

confidence: 99%

TRP Channels as Lower Urinary Tract Sensory Targets

Andersson

2019

Medical Sciences

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“…The measurement was carried out as previously described 14 . After the injection of carrageenan or saline into the prostate, a PE‐50 polyethylene catheter (Clay Adams, Parsippany, NJ) with a cuff was implanted into the bladder through the bladder dome and secured by a purse‐string suture with a 5‐0 silk thread.…”

Section: Methodsmentioning

confidence: 99%

“…The measurement was carried out as previously described. 14 After the injection of carrageenan or saline into the prostate, a PE-50 polyethylene catheter (Clay Adams, Parsippany, NJ) with a cuff was implanted into the bladder through the bladder dome and secured by a purse-string suture with a 5-0 silk thread. Seven days following implantation, each rat was placed in a metabolic cage (3701M081; Tecniplast) without restraint and was allowed to adapt for 2 hours before performing cystometrogram (CMG) at room temperature (22°C-24°C).…”

Section: Cystometry (Cystometrogram)mentioning

confidence: 99%

Bladder sensation evaluation of a carrageenan‐induced chronic prostatitis model using a direct measurement of the bladder mechanosensitive single‐unit afferent nerve activity

Aizawa

Yamanishi

Fujita

2020

Neurourology and Urodynamics

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Aims: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) causes long-standing pain and/or storage symptoms. This study aimed to evaluate the likelihood of deterioration of bladder sensation in a carrageenan-induced CP/ CPPS model by direct measurement of the bladder mechanosensitive singleunit afferent nerve activity. Methods: In this study, male adult Sprague-Dawley rats were used. They were injected 50 µL of 3% λ-carrageenan or its vehicle (saline) into both lobes of the ventral prostate. Seven days following injection, the pain behavior at the pelvic-perineal area (using von Frey filaments), prostatic blood flow (using a laser blood flowmeter), and histology were examined along with cystometry (under conscious free-moving condition) and mechanosensitive single-unit afferent nerve activity (under urethane anesthesia). Results: The prostate showed increased tissue weight and decreased blood flow and inflammatory cell infiltration in the carrageenan group compared to the control group. Consequently, the threshold of the pain behavior was decreased, and the basal and threshold pressures of the bladder were increased in the carrageenan group. In contrast, no significant differences of bladder histology and other cystometric parameters were found between the groups. Regarding Aδ-or C-fibers, the mechanosensitive afferent nerve activities revealed no differences in either group. Conclusions: The carrageenan-induced CP/CPPS rat model showed edema, ischemia, and inflammatory pain in the prostate, whereas a little change was detected in bladder sensation. These findings, which were evaluated using a direct measurement of the mechanosensitive single-unit afferent nerve activity, suggest that the bladder sensation is unlikely deteriorated in this model.

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“…For example bradykinin, a proinflammatory mediator, exerts an inhibitory effect on TRPM8 activity, while TRPM8 activation by cold causes downregulation of proinflammatory TNFα [ 189 ]. TRPM8 antagonist RQ-00434739 reduced activity of afferents in bladder inflammation [ 190 ]. Systemic application of PF-05105679 successfully inhibited the cold pressor response of human subjects, but also led to unexpected hot sensations (discontinued after phase I completed in 2011) [ 191 ].…”

Section: Effects Predominantly or Exclusively On Sensory Neuronsmentioning

confidence: 99%

Novel Analgesics with Peripheral Targets

Ciotu

Fischer

2020

Neurotherapeutics

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A limited number of peripheral targets generate pain. Inflammatory mediators can sensitize these. The review addresses targets acting exclusively or predominantly on sensory neurons, mediators involved in inflammation targeting sensory neurons, and mediators involved in a more general inflammatory process, of which an analgesic effect secondary to an anti-inflammatory effect can be expected. Different approaches to address these systems are discussed, including scavenging proinflammatory mediators, applying anti-inflammatory mediators, and inhibiting proinflammatory or facilitating anti-inflammatory receptors. New approaches are contrasted to established ones; the current stage of progress is mentioned, in particular considering whether there is data from a molecular and cellular level, from animals, or from human trials, including an early stage after a market release. An overview of publication activity is presented, considering a IuPhar/BPS-curated list of targets with restriction to pain-related publications, which was also used to identify topics.

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RQ-00434739, a novel TRPM8 antagonist, inhibits prostaglandin E2-induced hyperactivity of the primary bladder afferent nerves in rats

Cited by 17 publications

References 28 publications

TRP Channels as Lower Urinary Tract Sensory Targets

TRP Channels as Lower Urinary Tract Sensory Targets

Bladder sensation evaluation of a carrageenan‐induced chronic prostatitis model using a direct measurement of the bladder mechanosensitive single‐unit afferent nerve activity

Novel Analgesics with Peripheral Targets

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