Deciphering spinal endogenous dopaminergic mechanisms that modulate micturition reflexes in rats with spinal cord injury

Abstract

Spinal neuronal mechanisms regulate recovered involuntary micturition after spinal cord injury (SCI). It is recently discovered that dopamine (DA) is synthesized in the rat injured spinal cord and is involved in lower urinary tract (LUT) activity. To fully understand the role of spinal DA-ergic machinery in micturition, we examined urodynamic responses in female rats during pharmacological modulation of the DA pathway. Three to four weeks after complete thoracic SCI, L-DOPA administered intravenously during bladder cystometrogram and external urethral sphincter (EUS) electromyography reduced bladder overactivity and increased the duration of EUS bursting, leading to remarkably improved voiding efficiency. Apomorphine, a non-selective dopamine receptor (DR) agonist, or quinpirole, a selective DR₂ agonist, induced similar responses whereas a specific DR₂ antagonist remoxipride alone only had minimal effects. Meanwhile, administration of SCH 23390, a DR₁ antagonist, reduced voiding efficiency by increasing tonic EUS activity and shortening the EUS bursting period. Unexpectedly, SKF 38393, a selective DR₁ agonist, increased EUS tonic activity, implying a complicated role of DR₁ in LUT function. In metabolic cage assays, subcutaneous administration of quinpirole decreased spontaneous voiding frequency and increased voiding volumes; while L-DOPA and apomorphine were inactive possibly due to slow entry into the CNS. Collectively, tonically active DR₁ in SCI rats inhibits urine storage and enhances voiding by differentially modulating the EUS tonic and bursting patterns, respectively; while pharmacologic activation of DR₂ which are normally silent improves voiding by enhancing EUS bursting. Thus, enhancing DA signaling achieves better detrusor-sphincter coordination to facilitate micturition function in SCI rats.

Significance Statement

We employed pharmacological interventions of spinal endogenous dopaminergic (DA-ergic) pathways to decode the machinery of the bladder and sphincter reflexes in female rats with spinal cord injury (SCI). Consequently, tonically active D₁-like receptor (DR₁) in SCI rats inhibits urine storage and enhances voiding by differentially modulating the external urethral sphincter (EUS) tonic and bursting patterns, respectively; while pharmacologic activation of DR₂ which are normally silent improves voiding by increasing EUS bursting. Enhancing DA signaling with L-DOPA or apomorphine achieves better detrusor-sphincter coordination to facilitate micturition function in SCI rats. Therefore, spinal DA-ergic mechanisms play an important role in the recovered micturition function and may serve as a novel therapeutic target after SCI.