Induction of Bladder Sphincter Dyssynergia By κ-2 Opioid Receptor Agonists in the Female Rat

Abstract

The nonselective kappa opioid receptor agonist ethylketocyclazocine suppresses external urethral sphincter (EUS) reflexes in cats. We examined the role of spinal kappa-opioid receptor subtypes in the control of EUS function in rats using selective kappa-1 (U-50,488) or kappa-2 (GR-89,696) opiate receptor agonists. Urethane anesthetized female rats were catheterized through the bladder dome for cystometry. EUS function was assessed electromyographically. Drugs were administered intrathecally or intravenously. Micturition in rats is accompanied at different times by tonic (continuous) EUS spike activity and by phasic bursts of spikes separated by pauses. GR-89,696 (0.05 to 5 microg intrathecally) caused a dose dependent decrease in the number of bursts per micturition without affecting spike frequency within individual bursts or during periods of tonic activity. It resulted in decreased voiding efficiency and at high doses dyssynergia and overflow incontinence. The nonselective opiate receptor antagonist naloxone (1 mg/kg intravenously) blocked GR-89,696 effects. U-50,488H (0.05 to 15 microg intrathecally) caused no change in cystometric parameters or in EUS-electromyography. Efficient voiding in rats depends on a spinal pattern generator causing EUS motor neuron firing to occur in bursts, resulting in rapid urethral contraction and relaxation. Intrathecal kappa-2-opiate receptor agonists suppress this pattern generator, decreasing the number of bursts occurring during each micturition without decreasing motor neuron spike frequency during individual bursts or during tonic spike activity associated with urethral closure. Resultant dyssynergia leads to decreased voiding efficiency. The relevance of kappa-2 opioid receptors should be explored in higher species, especially regarding spinal cord injury induced dyssynergia.