Parkinson’s disease (PD) is frequently associated with lower urinary tract dysfunction, including urinary incontinence. Detrusor overactivity has been extensively studied as a major cause of urinary symptoms in PD, however, there have been few reports regarding urethral continence mechanisms [1]. Especially, the role of dopamine receptor-mediated pathways in stress-induced urethral continence reflexes, such as coughing or sneezing, remains unclear. We hypothesized that dopamine receptor-mediated urethral continence mechanisms are altered in PD. Therefore, this study aimed to investigate dopamine receptor-mediated urethral continence reflexes using sneeze-induced continence testing and leak point pressure analysis in a 6-hydroxydopamine (6-OHDA) rat model of PD.

Female Sprague-Dawley rats were used. PD rats were created by unilateral microinjection of 6-OHDA into the substantia nigra pars compacta. PD model establishment was evaluated by the apomorphine-induced rotation test, and dopaminergic neuronal loss was confirmed by tyrosine hydroxylase immunostaining. Urethral continence function was assessed by a sneeze-induced urethral continence reflex test (sneeze test) and a tilt leak point pressure (LPP) test. In the sneeze test, amplitude of urethral response (AUR), urethral baseline pressure (UBP), and amplitude of abdominal pressure response (APabd) were measured in intact and PD rats before and after cumulative intravenous apomorphine administration (0.001-1 mg/kg), with or without dopamine receptor antagonists (D1/2). In the LPP test, LPP was measured before and after cumulative apomorphine administration. Comparisons were performed using the Mann-Whitney U-test, with p < 0.05 considered significant.

The PD model was successfully established in approximately 79% of rats on the rotation test. In the sneeze test, pre-drug UBP did not differ significantly between intact and PD rats (20.64 ± 1.27 vs. 17.77 ± 1.55 cmH2O, p = 0.17). Because AUR may be influenced by sneeze intensity, urethral continence reflex activity was evaluated as the ratio of AUR to APabd (AUR/APabd). Pre-drug AUR/APabd was significantly lower in PD rats than in intact rats (4.19 ± 0.69 vs. 6.60 ± 0.64, p = 0.0089). In both groups, apomorphine decreased AUR/APabd, and this effect was prevented by a dopamine D2 receptor antagonist (remoxipride hydrochloride at the dose of 1 mg/kg iv, Fig. 1a). In the LPP test, pre-drug LPP was significantly lower in PD rats than in intact rats (42.5 ± 1.6 vs. 53.7 ± 3.3 cmH2O, p = 0.019). After apomorphine 0.1 mg/kg, LPP was significantly increased up to 49.5 ± 1.7 cmH2O in PD rats (p = 0.022), but it did not differ in intact rats (55.6 ± 2.5 cmH2O, Fig. 1b).

These findings indicate that urethral continence mechanisms are impaired in the PD model. The reduced AUR/APabd in the sneeze test suggests attenuation of an active urethral continence reflex during sneezing by D2 supraspinal pathways. In contrast, the reduced LPP and apomorphine-induced increase in the PD model indicates impairment of spinal D1/2 mediated urethral closure mechanisms recruited during passive increases in intravesical pressure, so called a guarding reflex (Fig. 2). The different responses to apomorphine in the sneeze test and LPP test, together with the reversal by D2 receptor antagonism in the sneeze test, suggest that optimizing PD treatment will require a nuanced approach that balances these two mechanisms. Success lies in developing therapies that can selectively enhance continence without triggering the inhibitory effects of supraspinal D2 stimulation.

Distinct dopamine receptor-mediated pathways contribute to urethral continence in a rat model of PD. Impairment of these mechanisms may underlie urinary incontinence in PD and may offer new targets for therapeutic intervention.

Miyazato M, Kadekawa K, Kitta T, Wada N, Shimizu N, de Groat WC, Birder LA, Kanai AJ, Saito S, Yoshimura N. New frontiers of basic science research in neurogenic lower urinary tract dysfunction. Urol Clin North Am. 2017;44(4):491-505. doi:10.1016/j.ucl.2017.04.014.

Continence 19S (2026) 102589
DOI: 10.1016/j.cont.2026.102589