The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats

Gandaglia, Giorgio; Strittmatter, Frank; Croce, Giovanni La; Benigni, Fabio; Bettiga, Arianna; Castiglione, Fabio; Moschini, Marco; Mistretta, Francesco A.; Gratzke, Christian; Montorsi, Francesco; Stief, Christian G.; Hedlund, Petter

doi:10.1002/nau.22482

Cited by 16 publications

(16 citation statements)

References 31 publications

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“…The effects by PGE 2 in the bladder are suggested to be mediated by sensitization of afferent nerves and by modulation of efferent neurotransmission (Andersson and Wein, 2004;Aizawa et al, 2010); in agreement with our previous experience, infusion of PGE 2 into bladders of vehicle controls caused bladder overactivity with increased frequency, decreased micturition volume, and increased pressures (Gandaglia et al, 2014). These effects were not observed in rats treated with intravesical DFL23448.…”

Section: Trpm8 As a Drug Target In Models For Bladder Overactivitysupporting

confidence: 86%

DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats

Mistretta

Russo

Castiglione

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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The transient receptor potential melastin 8 ion channel (TRPM8) is implicated in bladder sensing but limited information on TRPM8 antagonists in bladder overactivity is available. This study characterizes a new TRPM8-selective antagonist (DFL23448 [5-(2-ethyl-2H-tetrazol-5-yl)-2-(3-fluorophenyl)-1,3-thiazol-4-ol]) and evaluates it in cold-induced behavioral tests and tests on bladder function and experimental bladder overactivity in vivo in rats. DFL23448 displayed IC 50 values of 10 and 21 nM in hTRPM8 human embryonic kidney 293 cells activated by Cooling Agent 10 or cold, but it had limited activity (IC 50 . 10 mM) at transient receptor potential vanilloids TRPV1, TRPA1, or TRPV4 or at various G protein-coupled receptors. In rats, DFL23448 administered intravenously or orally had a half-life of 37 minutes or 4.9 hours, respectively. DLF23448 (10 mg/kg i.v.) reduced icilininduced "wet dog-like" shakes in rats. Intravesical DFL23448 (10 mg/l), but not vehicle, increased micturition intervals, micturition volume, and bladder capacity. During bladder overactivity by intravesical prostaglandin E 2 (PGE 2 ), vehicle controls exhibited reductions in micturition intervals, micturition volumes, and bladder capacity by 37%-39%, whereas the same parameters only decreased by 12%-15% (P , 0.05-0.01 versus vehicle) in DFL23448-treated rats. In vehicle-treated rats, but not in DFL23448-treated rats, intravesical PGE 2 increased bladder pressures. Intravenous DFL23448 at 10 mg/kg, but not 1 mg/kg DFL23448 or vehicle, increased micturition intervals, micturition volumes, and bladder capacity. During bladder overactivity by intravesical PGE 2 , micturition intervals, micturition volumes, and bladder capacity decreased in vehicle-and 1 mg/kg DFL23448-treated rats, but not in 10 mg/kg DFL23448-treated rats. Bladder pressures increased less in rats treated with DFL23448 10 mg/kg than in vehicle-or 1 mg/kg DFL23448-treated rats. DFL23448 (10 mg/kg i.v.), but not vehicle, prevented cold stress-induced bladder overactivity. Our results support a role for bladder TRPM8-mediated signals in experimental bladder overactivity.

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Section: Trpm8 As a Drug Target In Models For Bladder Overactivitysupporting

confidence: 86%

DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats

Mistretta

Russo

Castiglione

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…Treatment with a FAAH inhibitor increased voiding intervals, voiding volume and bladder capacity in normal rats via activation of cannabinoid 2 (CB2) receptors (Strittmatter et al, 2012) and rats with bladder overactivity (Gandaglia et al, 2013). Furthermore, FAAH inhibition attenuated afferent activity induced by bladder distension via activation of both cannabinoid 1 (CB1) and CB2 (Aizawa et al, 2014) and suppressed referred hyperalgesia associated with bladder inflammation (Merriam et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Attenuation of Cystitis and Pain Sensation in Mice Lacking Fatty Acid Amide Hydrolase

Wang

Hillard

et al. 2014

J Mol Neurosci

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Endocannabinoids, such as N-arachidonylethanolamine (AEA, also called anandamide), exert potent analgesic and anti-inflammatory effects. Fatty acid amide hydrolase (FAAH) is primarily responsible for degradation of AEA, and deletion of FAAH increases AEA content in various tissues. Since FAAH has been shown to be present in the bladder of various species, we compared bladder function, severity of experimental cystitis, and cystitis-associated referred hyperalgesia in male wild type (WT) and FAAH knock-out (KO) mice. Basal concentrations of AEA were greater, and the severity of cyclophosphamide (CYP)-induced cystitis was reduced in bladders from FAAH KO compared to WT mice. Cystitis-associated increased peripheral sensitivity to mechanical stimuli and enhanced bladder activity (as reflected by increased voiding frequency) were attenuated in FAAH KO compared to WT mice. Further, abundances of mRNA for several pro-inflammatory compounds were increased in bladder mucosa after CYP treatment of WT mice, and this increase was inhibited in FAAH KO mice. These data indicate that endogenous substrates of FAAH, including the cannabinoid AEA, play an inhibitory role in bladder inflammation and subsequent changes in pain perception. Therefore, FAAH could be a therapeutic target to treat clinical symptoms of painful inflammatory bladder diseases.

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“…The CB1 antagonist AM251 (1 mM) was instilled into bladders of FAAH KO mice 30 minutes prior to treatment with NGF. The dosage of ACEA was chosen based on previous publications relevant to the present study [10, 40]. The affinity of ACEA and AM251 to CB1 receptors is 1.4 and 7.5 nM, respectively (Tocris).…”

Section: Methodsmentioning

confidence: 99%

Activation of cannabinoid receptor 1 inhibits increased bladder activity induced by nerve growth factor

Wang

Bjorling

2015

Neuroscience Letters

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Nerve growth factor (NGF) is an important mediator of inflammatory pain, in part by sensitizing afferent nerve fibers, and expression of NGF is increased during bladder inflammation. We investigated whether intravesical instillation of the selective cannabinoid receptor 1 (CB1) agonist arachidonyl-2'-chloroethylamide (ACEA) affects NGF-induced increased bladder activity in female C57BL/6J wild-type (WT) mice. We also examined the effects of intravesical NGF in female fatty acid amide hydrolase knock-out (FAAH KO) mice. We found that CB1 and tyrosine kinase A (trkA, the high-affinity NGF receptor) were present in L6 dorsal root ganglion (DRG) afferent neurons and in bladders of both genotypes. Intravesical NGF increased bladder activity that was inhibited by intravesical ACEA in WT mice. The inhibitory effects of ACEA were reversed by the selective CB1 antagonist AM 251. Intravesical NGF failed to affect bladder activity in FAAH KO mice, and treatment with AM251, restored the stimulatory effects of NGF on the bladder in FAAH KO mice. These results indicate that activation of CB1 inhibits increased bladder activity induced by NGF.

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The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats

Cited by 16 publications

References 31 publications

DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats

DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats

Attenuation of Cystitis and Pain Sensation in Mice Lacking Fatty Acid Amide Hydrolase

Activation of cannabinoid receptor 1 inhibits increased bladder activity induced by nerve growth factor

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