The purpose of this study is to determine whether duloxetine (a serotonin-norepinephrine reuptake inhibitor) combined with transcutaneous foot stimulation or WAY100635 (a 5HT1A antagonist) can enhance inhibition of bladder overactivity in cats. Cystometrograms were performed on 8 cats under α-chloralose anesthesia by infusing saline and then 0.25% acetic acid (AA) to induce bladder overactivity. To inhibit bladder overactivity, foot stimulation (5 Hz) was applied via transcutaneous pad electrodes to the right hind foot at 2 and 4 times the threshold (T) intensity for inducing a toe twitch. Duloxetine (0.003-3 mg/kg) was administered intravenously to determine the effect of combination treatment. After the 3 mg/kg dose of duloxetine, WAY100635 (0.5 mg/kg) was given intravenously. AA irritation significantly (P<0.0001) reduced bladder capacity to 42.7±7.4% of saline control capacity. Foot stimulation alone at both 2T and 4T significantly (P<0.0001) inhibited bladder overactivity and increased bladder capacity to 66.7±6.3% and 85.7±6.5% of saline control, respectively. Duloxetine alone dose-dependently inhibited bladder overactivity and completely restored bladder capacity to saline control (109±15.5%) at 3 mg/kg. Although duloxetine combined with foot stimulation did not further enhance the inhibition, WAY100635 (0.5 mg/kg) given after 3 mg/kg duloxetine further increased (P=0.008) bladder capacity to 162.2±22.5% of saline control. Although duloxetine and foot stimulation independently inhibited bladder overactivity, combined treatment did not enhance the inhibition. Duloxetine combined with WAY100635, however, synergistically enhanced bladder inhibition, indicating a potential novel treatment for overactive bladder if duloxetine is combined with a 5HT_1A receptor antagonist drug.