Effect of duloxetine, a norepinephrine and serotonin reuptake inhibitor, on sneeze-induced urethral continence reflex in rats

Abstract

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 (it) methiothepin maleate (5-HT receptor and alpha1-adrenoceptor antagonist) or terazosin or idazoxan (selective alpha1- and alpha2-adrenoceptor antagonists, respectively). Amplitude of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal adult female rats and rats with SUI induced by vaginal distension (VD). In normal and VD rats, intravenous application of duloxetine (1 mg/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 from 39.1 to 92.2 cmH2O by intravenous duloxetine in incontinent VD rats. Duloxetine-mediated enhancement of A-URS was inhibited by terazosin but not methiothepin maleate (it). In addition, simultaneous intrathecal application of methiothepin and terazosin induced a reduction in A-URS during sneezing, which was not increased by intravenous duloxetine. However, the reduced A-URS after intrathecal application of methiothepin and terazosin returned to the control level when duloxetine (iv) was applied after intrathecal 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.

Fig. 1.

Representative traces of urethral and abdominal pressure changes before and after duloxetine (1 mg/kg iv) in a normal (A) and a vaginal distension (VD) rat (B). a: Urethral pressure response measured by a microtransducer-tipped catheter inserted to the midurethra from the urethral orifice. b: Abdominal pressure measured by a balloon catheter inserted into the abdominal cavity. Sneeze-induced increases in urethral and abdominal pressures were simultaneously recorded. Duloxetine enhanced amplitude of urethral responses during sneezing (A-URS) and also increased urethral baseline pressure (UBP).

Fig. 2.

Representative traces of urethral (a) and abdominal (b) pressure changes induced by duloxetine (1 mg/kg iv) in the presence of intrathecal (it) methiothepin maleate (A), terazosin (B), coapplication of methiothepin maleate and terazosin (C), and coapplication of methiothepin maleate and terazosin followed by idazoxan (D). A: methiothepin maleate (6 nmol it) alone did not affect the sneeze-induced urethral response or the duloxetine-induced increase in A-URS and UBP. B: terazosin (2 nmol it) alone did not affect the sneeze-induced urethral response. However, in the presence of terazosin, the duloxetine-induced increase in A-URS was suppressed. The duloxetine-induced increase in UBP was still observed. C: coapplication (it) of methiothepin maleate (6 nmol) and terazosin (2 nmol) suppressed the sneeze-induced urethral response. In the presence of methiothepin maleate and terazosin, the duloxetine-induced increase in A-URS was further suppressed, with slight elevation in UBP. D: coapplication (it) of methiothepin maleate (6 nmol) and terazosin (2 nmol) suppressed the sneeze-induced urethral response as seen in C. However, in the presence of methiothepin maleate and terazosin, subsequent application (it) of idazoxan abolished the duloxetine-induced decrease in A-URS. The duloxetine-induced increase in UBP was decreased.

Fig. 3.

Hypothetical schema shows the roles of noradrenergic and serotonergic pathways in sneeze-induced urethral continence reflexes. A: at the spinal level. Descending signals of bulbospinal noradrenergic and serotonergic pathways enhance activity of spinal excitatory interneurons (e.g., glutamatergic neurons) or the Onuf's nucleus directly via α₁-adrenoceptors and 5-hydroxytryptamine (5-HT) receptors, thereby maintaining the sneeze-induced active urethral closure mechanisms, while α₂-adrenoceptor stimulation by noradrenergic pathways can inhibit activity of the Onuf's nucleus. Duloxetine enhances these descending pathways to enhance the sneeze-induced continence reflex. B: at the peripheral level. Duloxetine can increase norepinephrine (NE) levels at sympathetic postganglionic nerve terminals, leading to activation of peripheral α₁-adrenoceptors in urethral smooth muscles, and increase urethral baseline pressure. ACh, acetylcholine.