We investigated the effect of duloxetine, a norepinephrine (NE) and serotonin (5-HT) reuptake inhibitor, on the neurally evoked urethral continence reflex induced by sneezing in rats. To clarify the role of noradrenergic and serotonergic mechanisms in preventing stress urinary incontinence (SUI) during sneezing, we examined the effect of duloxetine followed by intrathecal (i.t.) methiothepin maleate (5-HT receptor and ₁-adrenoceptor antagonist), terazosin or idazoxan (selective ₁ or ₂-adrenoceptor antagonists, respectively). Amplitudes of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the mid-urethra and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats and rats with SUI induced by vaginal distention (VD). In normal and VD rats, intravenous (i.v.) application of duloxetine (1mg/kg) increased A-URS by 35 and 34% and UBP by 21 and 34%, respectively. Sneezing induced fluid leakage from the urethral orifice was observed in VD rats, but not in normal rats. S-LPP was increased 39.1 to 92.2 cmH₂O by i.v. duloxetine in incontinent VD rats. Duloxetine-mediated enhancement of A-URS was inhibited by terazosin, but not methiothepin maleate (i.t.). In addition, simultaneous i.t. application of methiothepin and terazosin induced a reduction in A-URS during sneezing, which was not increased by i.v. duloxetine. However, the reduced A-URS after i.t. application of methiothepin and terazosin returned to the control level when duloxetine (i.v.) was applied following i.t. idazoxan administration. These results indicate that duloxetine can prevent SUI by facilitating noradrenergic and serotonergic systems in the spinal cord to enhance the sneeze-induced active urethral closure mechanism.