Urothelial Cell Modulation of Sensory Nerve Activity

Interstitial cystitis/bladder pain syndrome is a devastating disease with minimal therapeutic options. While the disease pathophysiology is poorly understood, urothelial cells are proposed to play a critical role in the modulation of sensory neurons in the bladder and contribute to disease pathology. It is challenging to determine the exact role of these cells in sensory signaling, in part because multiple cell types in the bladder express the same sensory receptors making it challenging to interpret pharmacological studies. To overcome this challenge, we have developed a novel murine model where the urothelial cells express channelrhodopsin-2 (ChR2), a nonselective cation channel that allows for direct stimulation of urothelial cells with light. Initial validation indicates optical stimulation of these urothelial cells initiates the release of adenosine triphosphate (ATP), a nociceptive signaling molecule, like other types of physiological stimulation of these cells. We hypothesize that activation of urothelial cells and subsequent release of signaling molecules, including ATP, modulates sensory neuron activity and influences bladder sensory function. Preliminary recordings of visceromotor responses (VMR), an indirect measure of bladder nociception, indicate direct stimulation of urothelial cells increases nociceptive response in animals with bladder inflammation. Additionally, cystometry recordings demonstrate that optical stimulation of urothelial cells increases bladder pressure and increases pelvic nerve activity. Collectively, our data suggest that urothelial cells can influence bladder sensory nerves and potentially nociception. The data collected aids in furthering our understanding of urothelial-sensory neuron signaling and is a foundation for further studies on how communication changes with disease progression.