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Sources of Funding: National Institutes of Diabetes, Digestive and Kidney Diseases under Grants DK-094905, DK-102427, and DK-091253.

Introduction

Tibial and pudendal nerve stimulation (TNS and PNS) have been shown to be effective in the management of overactive bladder (OAB). Substantial questions about their mechanisms of action remain. In prior studies, baclofen (GABAB receptor agonist) has been shown to induce both spinal and supraspinal inhibition of micturition. We hypothesized that tibial or pudendal neuromodulation activates GABAB to inhibit bladder overactivity. CGP52432 (a GABAB receptor antagonist) was administered to cats after inducing bladder overactivity to evaluate its ability to extinguish the inhibition of TNS and PNS.

Methods

OAB was induced by performing serial cystometrograms (CMGs) with 0.5% acetic acid. The pudendal or tibial nerves (10 cats in each group divided equally within groups by sex) were isolated and stimulated (5Hz, 0.2ms) at 2 and 4 times threshold (2T or 4T) to produce an anal or hindlimb reflex respectively. CMGs during TNS and PNS were repeated to determine a new control capacity. Increasing doses of CGP52432 were then administered intravenously. CMGs were repeated at 2T and 4T to evaluate the ability of GABAB blockade to extinguish the increase in bladder capacity produced by TNS and PNS.

Results

TNS and PNS inhibited bladder overactivity induced by AA irritation and significantly (p<0.05) increased bladder capacity. TNS increased capacity to 173.8±16.2% and 198.5±24.1% of control capacity at 2T and 4T and PNS increased capacity to 217±18.8% and 221.3±22.3%. CGP52432 at doses of 0.1- 1.0 mg/kg completely (p<0.05) removed the inhibition induced by 2T and 4T TNS in female cats but not males (Figure 1). In contrast, PNS inhibition of bladder overactivity was not abolished by CGP52432 in either female or male cats (Figure 2).

Conclusions

There is a sex specific response to GABAB receptors inhibition in tibial but not pudendal neuromodulation of OAB. This data supports a GABAB receptor dependent mechanism for tibial neuromodulation of bladder overactivity in female animals.

Funding

National Institutes of Diabetes, Digestive and Kidney Diseases under Grants DK-094905, DK-102427, and DK-091253.