Dopaminergic D2 receptors activate PKA to inhibit spinal pelvic-urethra reflex in rats

Abstract

To clarify the role of descending dopaminergic innervation in reflexive urethral closure, the impacts of dopaminergic D2 receptor (DR2)-selective agonists and antagonists on repetitive stimulation-induced pelvic-to-urethra spinal reflex potentiation (SRP) were tested using in vivo rat preparations. Pelvic afferent nerve test stimulation (TS; 1 pulse/30 s for 30 min) evoked baseline reflex activity with single spikes in the external urethral sphincter electromyogram (EUSE), whereas, repetitive stimulation (RS; 1 pulse/s for 30 min) induced SRP. Intrathecal application of quinelorane dihydrochloride (Q110; 10, 30, and 100 nM, 10 μl, a selective DR2 agonist) dose dependently inhibited the RS-induced SRP. Pretreatment with L135 (100 nM, 10 μL it, a selective DR2 antagonist) antagonized the Q110-dependent inhibition (100 nM, 10 μl it). Intrathecal AMPA (10 μM, 10 μl, a selective glutamatergic AMPA receptor agonist), and NMDA (10 μM, 10 μl, a selective glutamatergic NMDA receptor agonist) reversed the Q110-dependent inhibition. Intrathecal forskolin (100 nM, 10 μl, a PKA activator) prevented the Q110-dependent inhibition that was reversed by CNQX (10 μM, 10 μl it, a selective glutamate AMPA receptor antagonist) and APV (10 μM, 10 μl it , a selective glutamate NMDA receptor antagonist). Our results suggest that DR2 activation, which inactivates intracellular PKA, may be involved in descending dopaminergic inhibition of NMDA/AMPA receptor-dependent SRP at the lumbosacral spinal cord, which is thought to be involved in reflexive urethral closure.