The normal sensations of bladder filling appear to be mediated by small myelinated A-δ fibers. However, C-fiber afferents, which are small and unmyelinated, have very high mechanical thresholds and do not respond to even high levels of intravesical pressure. C-fibers are activated by noxious chemical irritation or by cold. In the irritated state, these fibers become responsive to low-pressure bladder distension–like mechanoreceptive A-δ fibers. C-fibers, therefore, are normally “silent” and appear to have a specific function, ie, signaling of inflammatory or noxious events in the bladder (Chancellor and de Groat, J Urol 162: 3–11, 1999). The vanilloids, capsaicin and resiniferatoxin, activate nociceptive sensory nerve fibers through an ion channel, recently discovered by Caterina et al. (Nature 389: 816, 1997), known as vanilloid receptor subtype 1 (VR1). This receptor is a nonselective cation channel and is activated by increases in temperature to within the noxious range and by protons, suggesting that it functions as a transducer of painful thermal stimuli and acidity in vivo. When activated, the channel opens, allowing an influx of calcium and sodium ions that depolarize the nociceptive afferent terminals, initiating a nerve impulse that travels through the dorsal root ganglion (DRG) into the central nervous system. Noxious temperature uses the same elements, which explains why the mouth feels hot when eating chili peppers (Clapham, Nature 389: 783, 1997). Previously called the capsaicin receptor, VR1 has been localized in the spinal cord, DRG, and visceral organs, including the bladder, urethra, and colon. Activation of VR1 results in spike-like currents (Liu and Simon, J Neurophysiol 75: 1503, 1996), and selectively excites and subsequently desensitizes C-fibers. Capsaicin desensitization is defined as long-lasting, reversible suppression of sensory neuron activity (Craft et al., Pain 61: 317, 1995).