Because all three components of lower urinary tract control (parasympathetic, sympathetic and somatic) are intimately associated with serotonin (5-hydroxytryptamine [5HT])- and norepinephrine (NE)- containing terminals and receptors, in the present study, we examined the effects of increasing extracellular levels of 5HT and NE with duloxetine, a 5HT and NE reuptake inhibitor, on lower urinary tract function under "normal" or nonirritated conditions (transvesical infusion of saline) and in a model of bladder irritation (i.e., transvesical infusion of 0.5% acetic acid) in chloralose-anesthetized cats. Irritation reduced bladder capacity (to 20% of control) and produced insignificant increases in periurethral electromyographic (EMG) activity compared with nonirritated control animals. Duloxetine produced insignificant increases in bladder capacity and sphincter EMG activity when administered under nonirritated bladder conditions. However, this duloxetine "pretreatment" did prevent the typical acetic acid-induced reductions in bladder capacity and unmasked a marked activation of sphincter EMG activity on acetic acid infusion (by 8-fold). Furthermore, when administered initially under irritated bladder conditions, duloxetine produced dose-dependent increases in bladder capacity (by 5-fold) and increased periurethral striated muscle EMG activity (by 8-fold). The effects on bladder activity were due to central mechanisms since bladder contractions evoked by direct electrical stimulation of efferent fibers in the pelvic nerve were not effected by duloxetine. The effects of duloxetine on bladder capacity were antagonized by methiothepin, a non-selective 5HT receptor antagonist, but not by the other 5HT and NE receptor antagonists examined: LY53857, a 5HT2 antagonist; prazosin, an alpha-1-adrenergic receptor antagonist; idazoxan, an alpha-2-adrenergic receptor antagonist; or propranolol, a beta-adrenergic receptor antagonist. The facilitatory effects of duloxetine on periurethral sphincter EMG were significantly antagonized to various degrees by methiothepin, LY53857 and prazosin but not by idazoxan or propranolol. These results indicate that duloxetine, through inhibition of 5HT and NE reuptake, has weak effects under normal conditions. However, under conditions of bladder irritation, duloxetine suppresses bladder activity through 5HT receptor mechanisms and enhances external urethral sphincter activity through 5HT2 and alpha-1-adrenergic mechanisms.