Role of Opioid and Metabotropic Glutamate 5 Receptors in Pudendal Inhibition of Bladder Overactivity in Cats

Abstract

Purpose We determined the role of opioid and metabotropic glutamate 5 receptors in the pudendal inhibition of bladder overactivity. Materials and Methods Cystometrograms were performed in 11 cats under α-chloralose anesthesia by slowly infusing the bladder with saline or 0.25% acetic acid. Pudendal nerve stimulation at intensities of multiple times the threshold to induce observable anal twitching was applied during cystometrogram to inhibit the bladder overactivity induced by acetic acid irritation. Naloxone (0.1, 0.3 and 1 mg/kg intravenously) was administered to block opioid receptors, followed by MTEP (3 and 10 mg/kg intravenously) to block metabotropic glutamate 5 receptors. After each drug dose, pudendal inhibition of bladder overactivity was examined during cystometrogram. Results Acetic acid irritated the bladder, induced bladder overactivity and significantly decreased mean ± SE bladder capacity to 23.6% ± 2.7% of saline control capacity. Pudendal nerve stimulation at 1 to 1.5 and 4 × threshold suppressed bladder overactivity and significantly increased mean capacity to 57.5% ± 8.1% (p = 0.0005) and 106% ± 15% (p = 0.0002), respectively, of saline control capacity. Naloxone had no effect on pudendal inhibition but MTEP eliminated the inhibition induced by low intensity stimulation and significantly decreased the inhibition induced by high intensity stimulation (p <0.05). Neither naloxone nor MTEP altered baseline bladder overactivity. Conclusions Opioid receptors are not involved in pudendal inhibition of bladder overactivity but metabotropic glutamate 5 receptors are partially involved. Understanding neurotransmitter mechanisms could improve the efficacy of neuromodulation therapy for overactive bladder and identify molecular targets for developing new drugs for overactive bladder.

A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation

“…Post hoc paired comparisons with Bonferroni correction showed that while normalized bladder pressure was significantly higher with picrotoxin (*P Ͻ 0.001), there was no significant difference between control, paralytic, and washout trials. contributions of opioidergic mechanisms to stimulationevoked bladder inhibition (7,28). The present results reveal that a spinal GABAergic mechanism mediates the inhibitory pudendovesical pathway.…”

“…Inhibition of bladder contractions evoked by the infusion of AA, but not saline, with tibial nerve stimulation was blocked by naloxone (44). Later experiments demonstrated that naloxone had no effect on pudendal stimulation-evoked inhibition of bladder overactivity in cats (28). We found that inhibition by either PN or DNP stimulation remained intact following administration of naloxone across a range of doses and stimulation amplitudes.…”

“…To block glycinergic receptors, increasing cumulative doses of strychnine (n ϭ 4, 0.01-0.1 mg/kg iv) were administered, including to two animals who received cumulative doses up to 0.25 mg/kg iv (40). Increasing cumulative doses of naloxone (0.1-4.0 mg/kg iv), a competitive opioid antagonist, were administered to identify any opioidergic contribution to bladder inhibition (n ϭ 3), as this was ambiguous from prior studies (7,28).…”

“…Because AA infusion is frequently used as a model of OAB in animal models (28), this finding has important implications for research for the treatment of OAB. Following spinal cord injury, an alternate reflex pathway for bladder control emerges, driven by nociceptive C-fiber afferent activity from the bladder (20).…”

“…Initial studies suggested that pudendal afferent stimulation produced bladder inhibition via activation of sympathetic efferents in the hypogastric nerve, causing ␣-adrenergic receptor-mediated inhibition at the vesical ganglia and/or ␤-adrenergic receptor-mediated direct inhibition of the detrusor muscle (10,14,15,26), while recent studies suggest that other central mechanisms may play a role in pudendal afferent-evoked inhibition (28). Stimulation of afferents in the dorsal genital branch of the PN continued to produce robust bladder inhibition following bilateral transection of the hypogastric nerve and pharmacological blockade of ␣-and ␤-adrenergic receptors (55), challenging the notion that bladder inhibition with PN stimulation requires activation of sympathetic outflow and suggesting the existence of an alternate mechanism.…”