Urothelial 5-HT1DR and 5-HT4R-mediated inhibition may represent important endogenous protective mechanisms against hypersensitivity following bladder inflammation, as we found 5-HT4R−/− mice exhibited exaggerated bladder overactivity and afferent hypersensitivity in comparison with the WT mice following CYP-induced cystitis. Here, HTR4 is linked to chronic cystitis.