TRPM8 Agonism Reduces Urinary Bladder Contractility in a TRPV1-Dependent Manner

Transient Receptor Potential (TRP) channels, specifically TRPM8 and TRPV1, are expressed in bladder afferent nerves where they regulate sensory outflow to the CNS and bladder contractility. In expression systems, activation of TRPM8 channels inhibits responses to TRPV1 channel agonism and vice versa. However, it is unknown if this reciprocity exists in the urinary bladder and if it can affect nerve-evoked bladder contractions. Using isometric contractility, we tested the hypothesis that activating TRPM8 channels reduces nerve-evoked bladder contractions in a TRPV1-dependent manner. Urinary bladders from 10 to 16-week-old male C57Bl/6 mice were dissected into strips and mounted in a tissue bath for isometric contractility experiments. In some strips, the urothelium was removed by blunt dissection. Alone, the TRPV1 agonist capsaicin (100 nM) caused a transient contraction but did not alter contractions elicited by electrical field stimulation (0.5 – 50 Hz).The TRPM8 agonist menthol (300 µM) alone had no effect on contractions to the muscarinic agonist carbachol (10 nM – 10 µM), but significantly reduced contractions to electrical field stimulation that were unaffected by removal of the urothelium. Surprisingly, addition of capsaicin after menthol reversed this reduction in nerve-evoked contractions. Together, these data suggest that nerve-evoked contractile responses to TRPM8 channel activation in the urinary bladder are also reciprocally regulated by TRPV1 channels. Future experiments will determine which nerves express TRPV1 and TRPM8 channels and if disruption in this relationship can lead to bladder dysfunction. Funded by NIH grants R01-DK135696, R01-DK119615, P01-HL152951 and P20-DK127554. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.