PD7-07 A NOVEL TARGET FOR UNDERACTIVE BLADDER DISEASE: TRPV4 CATION CHANNEL ACTIVATION IMPROVES BLADDER FUNCTION IN A RAT MODEL FOR DETRUSOR UNDERACTIVITY

Abstract

INTRODUCTION AND OBJECTIVES: Pudendal nerve stimulation (PNS) reduces pain in humans with interstitial cystitis/bladder pain syndrome (IC/BPS) and the visceromotor response (VMR) to urinary bladder distension (UBD) in a rat model of bladder hypersensitivity. The effectiveness of PNSmay be impacted by pre-exposure of opioids which are commonly used in practice. To address co-administration concerns, the aim of this rat study was to evaluate if endogenous opioid system is involved in the neural control of bladder nociceptive reflex by PNS. METHODS: Bladder hypersensitivity was produced by neonatal bladder inflammation in female rat pups coupled with a second insult as an adult. Under urethane anaesthesia, wire electrodes were placed into the abdominal musculature to measure myoelectrical activity (VMR) to phasic UBD. Two pairs of hook electrodes were placed under each pudendal nerve bilaterally. The effects of PNS (10 Hz, pulse-width 0.1 ms) were assessed on VMR responses before and after the i.p. administration of saline or an opioid receptor antagonist naloxone hydrochloride (1 mg/kg). The effects of PNS were measured as percent change in VRMs ( SEM) compared to Area-under-the-Curve (AUC) of 0 Hz trial for VMRs evoked by 10, 20, 40 and 60 mmHg, 20 s UBD. RESULTS: PNS at 1xmotor threshold (Tmot) or 3xTmot produced statistically significant inhibition on VMRs to UBD. Such effects were frequency-dependent; maximal inhibitory effects produced by electrical stimulation of 5 Hz or greater (up to 100 Hz). Low frequencies of stimulation (0.1 and 1 Hz) did not produce decreases in VMR to UBD. Neither naloxone nor saline produced any statistically significant alternations on inhibitory effects of PNS (3xTmot, 10 Hz). The VMRs to PNS were decreased 26.9 4.0% and 30.9 7.9%, respectively before and after naloxone (p<0.05, repeated measure ANOVA). Similarly before and after saline injection, the VMRs to PNS were significantly decreased 31.9 8.4% and 25.2 8.3%, respectively (p<0.05). CONCLUSIONS: PNS inhibited the nociceptive response in a rat model of bladder hypersensitivity. The inhibitory effects of PNS could not be blocked by pretreatment of naloxone. Data from this study suggest the potential for clinical utility of PNS in reducing the symptoms of IC/BPS. Though the mechanism of this effect was not determined, the insensitivity to naloxone shows that non-opioid actions are involved in the pudendal neuromodulation on pain control and suggests potential utility of PNS in treating painful bladder syndromes like IC/BPS even when concomitant opioids are being utilized.