Sensitisation of low-threshold bladder afferent fibres to physiological distension following intravesical mitomycin C in mice

Abstract Purpose Intravesical mitomycin C (MMC) is commonly associated with urinary bladder dysfunction in patients. This study investigated the effect of intravesical MMC on bladder sensory nerve activity during bladder filling in an in vitro murine model. Methods Anaesthetised mice were treated intravesically with saline or MMC (1 mg/mL) for 60 min and 24 h later, bladders were isolated and set up for recording of afferent nerve activity during bladder filling and treatment with pharmacological agents. Results MMC treatment did not affect bladder compliance but enhanced overall afferent nerve activity throughout bladder filling. This enhancement was observed only in afferent fibres with a low threshold and wide dynamic range; those with a narrow dynamic range were not affected by MMC pretreatment, whilst activity in the minor population of high threshold fibres was depressed after MMC. Intravesical pressure responses to carbachol (1µM) or ATP (10µM) were not affected by MMC pretreatment. Capsaicin (100µM) depressed the rise in nerve activity during bladder filling in control experiments (50% depression), and this effect was reduced (only 20% depression) after MMC treatment ( P < 0.05). This effect of MMC was observed at both physiological pressures (up to 15mmHg) and at high pressures (40mmHg). Conclusions In conclusion, intravesical treatment with MMC results in an enhancement of overall sensory nerve responses to bladder filling, and this was due to a selective sensitization of low threshold, wide dynamic range, afferent fibres. Over the physiological range of pressures, afferent nerve activity was enhanced, which may explain the urinary urgency and frequency encounter by patients after MMC treatment.