Abstract: PD50-09
Sources of Funding: Grant-in-Aid for Scientific Research (15K01377 and 15K01376)

Introduction

Stress urinary incontinence (SUI) is the most common type of urinary incontinence in women. As the efficacy of pharmacotherapy for SUI is generally unsatisfactory, surgery seems to be the best option for achieving long-term continence. Thus, new effective drugs for SUI should be developed. Tramadol is widely used as an analgesic. It combines the effects of μ-opioid receptors with inhibition of serotonin and noradrenaline reuptake inhibitors. Both effects may be useful for treatment of SUI, but the efficacy of tramadol for SUI has not been examined yet. We previously established a rat model that can be used for examining the active urethral closure mechanism during sneezing. We therefore investigated the effect of tramadol on urethral continence reflex by using this model.

Methods

Healthy female rats and rats with SUI induced by vaginal distension (VD) were used. (1) The effects of tramadol on tilt leak point pressure (tilt LPP) were examined before and after intravenous (i.v.) injection of tramadol under urethane anesthesia in both rats. (2) To investigate the effect of tramadol on mid-urethral responses during sneezing, the amplitude of the urethral responses during sneezing (A-URS) and urethral baseline pressure (UBP) were measured by inserting a microtip transducer catheter in the middle urethra in both rats. (3) To confirm the effects of tramadol on μ-opioid receptors in the spinal cord, the effect of tramadol in the presence of intrathecal (i.t.) cyprodime, a selective μ-opioid receptor antagonist, was examined in the healthy rats.

Results

(1) Tilt LPP was lower in the VD rats than in the healthy rats (43.9 vs 48.6 cmH2O). Tramadol (i.v.) significantly increased the tilt LPP by 25.9% and 21.2% in the healthy and VD rats, respectively. (2) In the healthy rats, tramadol (i.v.) enhanced the A-URS and UBP by 37.0% and 74.9%, respectively. In the VD rats, tramadol administration also enhanced UBP by 11.1% but did not affect A-URS. (3) Administration of cyprodime alone (i.t.) did not affect A-URS and UBP. However, in the presence of cyprodime, tramadol-induced increases in A-URS were suppressed, while UBP was elevated significantly._x000D_ _x000D_

Conclusions

These results indicate that tramadol, a μ-opioid agonist, is effective for enhancing the active urethral continence reflex during sneezing at the spinal level (a microtip transducer catheter measurement), thereby preventing SUI (a LPP measurement). Therefore, activation of μ-opioid receptors in the spinal cord may be a new candidate treatment for SUI in humans.

Funding

Grant-in-Aid for Scientific Research (15K01377 and 15K01376)