Selective pharmacological blockade of the TRPV1 receptor suppresses sensory reflexes of the rodent bladder.
OBJECTIVE
We investigated the pharmacological effect of TRPV1 antagonists in anesthetized rodent models of bladder function.


METHODS
The TRPV1 antagonists JNJ17203212 and JYL1421 were evaluated in the anesthetized rat volume induced micturition reflex model. JNJ17203212 was further evaluated in this model in capsaicin (Sigma) desensitized rats, and in rat capsaicin and mouse citric acid models of irritant induced detrusor overactivity.


RESULTS
Systemic JNJ17203212 and JYL1421 administration in the anesthetized rat volume induced micturition reflex model resulted in an increased micturition threshold volume. JNJ17203212 also decreased bladder contraction amplitude but JYL1421 had no effect. Capsaicin desensitization significantly increased baseline micturition threshold volume and decreased bladder contraction amplitude in the volume induced micturition reflex model compared to those in sham treated controls and JNJ17203212 produced no further effect after capsaicin desensitization. JNJ17203212 was also effective in 2 models of irritant induced detrusor overactivity, preventing the decrease in micturition threshold volume and the increase in bladder contraction amplitude observed with intravesical instillation of 10 microM capsaicin, and the decreased voiding interval induced by intravesical citric acid.


CONCLUSIONS
The TRPV1 antagonists JNJ17203212 and JYL1421 increased the threshold for activation of the micturition reflex in the anesthetized rat volume induced micturition reflex model. This effect appeared to be mediated by capsaicin sensitive afferents. JNJ17203212 also inhibited detrusor overactivity induced by intravesical capsaicin and intravesical citric acid. These data extend our understanding of the role of TRPV1 in sensory modulation of the micturition reflex under nonirritant and inflammatory conditions.
Cefalu
Joseph S
JS
Roche Palo Alto, Palo Alto, California 94304, USA.
Guillon
Marlene A
MA
Burbach
Leah R
LR
Zhu
Quan-Ming
QM
Hu
Dong-Qing
DQ
Ho
Meghan J
MJ
Ford
Anthony P D W
AP
Nunn
Philip A
PA
Cockayne
Debra A
DA
D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D001743:Urinary Bladder / Q000502:physiology*
C500065:4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide; D000631:Aminopyridines; C466314:JYL 1421; D010879:Piperazines; D013449:Sulfonamides; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D013890:Thiourea; D002211:Capsaicin