Inhibition of bladder overactivity by duloxetine in combination with foot stimulation or WAY-100635 treatment in cats

Abstract

The purpose of this study was to determine whether duloxetine [a serotonin (5-HT)-norepinephrine reuptake inhibitor] combined with transcutaneous foot stimulation or WAY-100635 (a 5-HT1A antagonist) can enhance inhibition of bladder overactivity in cats. Cystometrograms were performed on eight 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 hindfoot at two and four times the threshold 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, WAY-100635 (0.5 mg/kg) was given intravenously. AA irritation significantly (P < 0.0001) reduced bladder capacity to 42.7 ± 7.4% of the saline control capacity. Foot stimulation alone at both two and four times the threshold intensity significantly (P < 0.0001) inhibited bladder overactivity and increased bladder capacity to 66.7 ± 6.3% and 85.7 ± 6.5% of the saline control, respectively. Duloxetine alone dose dependently inhibited bladder overactivity and completely restored bladder capacity to the saline control (109 ± 15.5%) at 3 mg/kg. Although duloxetine combined with foot stimulation did not further enhance inhibition, WAY-100635 (0.5 mg/kg) given after 3 mg/kg duloxetine further increased (P = 0.008) bladder capacity to 162.2 ± 22.5% of the saline control. Although duloxetine and foot stimulation independently inhibited bladder overactivity, combined treatment did not enhance inhibition. Duloxetine combined with WAY-100635, however, synergistically enhanced bladder inhibition, indicating a potential novel treatment for overactive bladder if duloxetine is combined with a 5-HT1A receptor antagonist drug.

Reflex neuromodulation of bladder function elicited by posterior tibial nerve stimulation in anesthetized rats

“…A potential factor contributing to this excitatory reflex involves the experimental setup. Unlike previous work that used isovolumetric conditions (5,16,30,31,33,(35)(36)(37)(38), our study used continuous (i.e., urodynamic) bladder infusion that provided constant and/or periodic neural feedback via pelvic and pudendal afferents during each repeated bladder filling and voiding. We speculate that the pudendal afferents may have played a significant role in unmasking this otherwise quiescent 50-Hz excitatory reflex.…”

Increasing bladder capacity by foot stimulation in rats with spinal cord injuries

“…The bladder capacity (BC) was defined as the bladder volume threshold to induce a bladder reflex contraction of large amplitude (>30 cmH 2 O) and long duration (>20 s) [ 9 , 10 ].…”

Does our limited knowledge of the mechanisms of neural stimulation limit its benefits for patients with overactive bladder? ICI-RS 2013

“…Glutamate receptors probably are involved in PNS‐ and PTNS‐mediated inhibition of bladder overactivity in cats. Serotonin receptors are also suggested to be involved in PNS‐mediated bladder inhibition, however, the serotonin reuptake inhibitor, duloxetine, did not exhibit additive benefits during TNS in cats . Opioid receptors, particularly type µ, were suggested to be involved in the effects of SNS and PNS in normal cat bladders.…”