The role of TRPM8 in the Guinea-pig bladder-cooling reflex investigated using a novel TRPM8 antagonist

Gardiner, Jennifer C.; Kirkup, Anthony J.; Curry, John Aloysius; Humphreys, Sian; O'Regan, P F B; Postlethwaite, Michael; Young, Kimberley C.; Kitching, Linda; Ethell, Brian T.; Winpenny, David; McMurray, Gordon

doi:10.1016/j.ejphar.2014.07.022

Cited by 26 publications

(40 citation statements)

References 36 publications

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“…The authors suggested that the BCR in DO reflects loss of central inhibition, which is necessary to elicit this reflex. Studies in guinea pig and rats have supported that the BCR involves TRPM8 channels. However, Du et al .…”

Section: Trp Channelsmentioning

confidence: 99%

Potential Future Pharmacological Treatment of Bladder Dysfunction

Andersson

2016

Basic Clin Pharma Tox

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In the last decades, a number of new antimuscarinic drugs have been introduced for treatment of the overactive bladder (OAB), defined symptomatically (OAB syndrome) or urodynamically (detrusor overactivity). Recently, three new drug principles have been approved for clinical use, the b 3 -adrenoceptor agonist, mirabegron, the phosphodiesterase-5 inhibitor, tadalafil and the blocker of afferent and efferent nerves, botulinum toxin. However, new alternatives are continuously being explored. OAB is a filling disorder, and ATP is involved in the generation of afferent impulses. One way of blocking the ATP afferent pathway is through the use of P2X3 receptor antagonists. In animal models, this strategy appears to work very well, but whether it translates effectively to man remains to be established. Evidence suggests that components of the endocannabinoid system are involved in regulation of bladder function. Clinical studies of cannabinoid extracts on LUTS are scarce and essentially restricted to patients with MS, and the results have so far not been convincing. Amplification of endocannabinoid activity by inhibiting their degradation via fatty acid amide hydrolase inhibitors may be an attractive approach, but no clinical experiences in OAB have been reported. Studies of the lower urinary tract have indicated that several transient receptor potential (TRP) channels, including TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1, are expressed in the bladder and may act as sensors of stretch and/or chemical irritation. Animal studies have shown that inhibition of these pathways can be effective for the reduction in bladder activity. However, the roles of these channels for normal function and in pathological states have not been established, and so far adverse effects (hyperthermia) have hampered development of antagonists.Lower urinary tract symptoms (LUTS) are generally divided into storage (irritative), voiding (obstructive) and post-micturition components [1]. Particularly, the storage disorder, overactive bladder (OAB), defined symptomatically as the OAB syndrome, or urodynamically as detrusor overactivity (DO), can have major effects on quality of life and social functioning. In addition to antimuscarinic drugs, which still constitute first-line pharmacological treatment of the LUTS/OAB, three new drug principles have recently been approved for clinical use, the b 3 -adrenoceptor agonist, mirabegron, the phosphodiesterase-5 inhibitor tadalafil and the blocker of afferent and efferent nerves, botulinum toxin, whose places in therapy still have to be established [2][3][4][5]. These drugs have good initial response rates, but are not effective in all patients, and alternatives are continuously being explored. There are many agents with theoretically interesting profiles that have been or still are considered as promising, but currently do not seem to be in active development (table 1). For example, nerve growth factor (NGF) and other neurotrophins have been suggested to be an interesting target for treatment and a bioma...

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Section: Trp Channelsmentioning

confidence: 99%

Potential Future Pharmacological Treatment of Bladder Dysfunction

Andersson

2016

Basic Clin Pharma Tox

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“…Transient receptor potential melastatin 8 (TRPM8) channel, a non‐selective cation channel, is known to be activated by low temperature (<8‐28°C) and chemical agents such as menthol and icilin . Several reports have demonstrated that TRPM8 channels are expressed in urothelial cells, in sensory nerve fibers within the urothelium and suburothelium of the bladder, and in L6 dorsal root ganglia (DRG) of rats and guinea pigs and are also expressed in the urothelial cells of the human bladder . We previously reported that TRPM8 channels may have a role in the activation of bladder afferent pathways during bladder filling in normal rats, and this effect was at least partly mediated via mechanosensitive C fibers .…”

Section: Introductionmentioning

confidence: 99%

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

Aizawa

Fujimori

Kobayashi

et al. 2018

Neurourology and Urodynamics

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“…33,42 While not a direct measure of the compounds ability to act as an analgesic, the assay did provide a direct measure of TRMP8-mediated pharmacology. Results from these studies indicated that a maximum unbound concentration (C max ) of drug between 254− 450 nM (∼3 × IC 50 ) would be sufficient to test the mechanism in clinical studies.…”

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confidence: 97%

Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain

Andrews

Forselles

Beaumont

et al. 2015

ACS Med. Chem. Lett.

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The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, a member of the melastatin subfamily, is activated by cold temperatures (<28 °C), and antagonists of this channel have the potential to treat cold induced allodynia and hyperalgesia. However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. We report herein the identification and optimization of a series of TRPM8 antagonists that ultimately led to the discovery of PF-05105679. The clinical finding with this compound will be discussed, including both efficacy and its ability to affect thermoregulation processes in humans.

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The role of TRPM8 in the Guinea-pig bladder-cooling reflex investigated using a novel TRPM8 antagonist

Cited by 26 publications

References 36 publications

Potential Future Pharmacological Treatment of Bladder Dysfunction

Potential Future Pharmacological Treatment of Bladder Dysfunction

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

Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain

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