Analgesic effect of TRPV4 blockade on bladder pain in chronic cystitis mice

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder disorder accompanied by urinary dysfunction and bladder pain. The bladder pain is often resistant to current analgesics, such as amitriptyline and gabapentin, and decreases the quality of life for patients with IC/PBS. Novel analgesics with greater efficacy are urgently required; however, the pain mechanism in IC/PBS is not fully understood. Transient receptor potential vanilloid-4 (TRPV4) is expressed in the bladder epithelium to detect the mechanical stimulation associated with cell swelling and shear stress. Some reports have shown the involvement of TRPV4 in urinary dysfunction in rodent models, but little is known about bladder pain. Therefore, we investigated whether TRPV4 could be involved in the bladder pain induced by cyclophosphamide (CYP) in mice. Repeated intraperitoneal injection of CYP at 150 mg/kg for 4 days produced mild edema with some infiltration of inflammatory cells in the bladder, and persistent mechanical hypersensitivity in the lower abdomen of mice. The phosphorylated TRPV4 was significantly increased in the bladder of chronic cystitis mice, although the level of TRPV4 mRNA and the distribution of TRPV4 were not changed in the bladder compared with vehicle-injected mice. The gene depletion of TRPV4 completely prevented mechanical hypersensitivity in chronic cystitis mice. In addition, oral administration of the TRPV4 antagonist, GSK2193874, inhibited mechanical hypersensitivity in these mice. These results show that the TRPV4 antagonist may become a therapeutic option for bladder pain in patients with IC/PBS.