Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, affecting approximately 1% of the population, with a rapidly increasing prevalence. Urinary bladder dysfunction is a particularly burdensome manifestation of autonomic dysfunction in PD, commonly presenting as urgency, increased frequency and nocturia. Despite its significant impact on quality of life, the underlying mechanisms of bladder dysfunction remain poorly understood and effective treatments are limited. Recent hypotheses on PD pathogenesis, based on symptom progression and neuroimaging data, suggest two main disease trajectories: a “brain-first” phenotype, in which pathology originates in the central nervous system and later spreads to peripheral organs, and a “body-first” phenotype, where pathology begins in the peripheral nervous system and subsequently propagates to the brain. In the latter, some non-motor symptoms may precede motor symptoms by several years.
We hypothesize that both central and peripheral neurodegenerative processes contribute to bladder dysfunction. However, the role of each system remains unclear. Therefore, the aim of this study is to explore urinary bladder function in experimental models of central and peripheral dopaminergic lesions, representing both phenotype origins, in order to better understand their respective contributions.

Male Sprague Dawley rats received either 1. unilateral injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle to induce central dopaminergic lesion to model a“brain-first” subtype; or 2. systemic, intraperitoneal, injections of 6-OHDA daily over three consecutive days at doses of 100 mg/kg, to model a “body-first” phenotype. As 6-OHDA does not cross the blood–brain barrier, the latter should selectively induce peripheral dopaminergic and noradrenergic lesions. In both models, control animals received saline instead of 6-OHDA.
Three to four weeks post-treatments, urination patterns were evaluated in metabolic cages. Animals were sacrificed and urinary bladders were collected for in vitro functional experiments and histological analyses. The functional in vitro smooth muscle responses were assessed using organ baths where the tissues were challenged with electrical field stimulation (EFS), the cholinergic agonist methacholine, the purinergic agonist ATP, and the adrenergic agonist noradrenaline
Data acquisition of micturition patterns and organ bath concentration–response curves was performed using AcqKnowledge software (v3.8). Concentration–response data was analysed using two-way ANOVA, while micturition data was analysed using a t-test. Histological analyses were conducted through quantitative fluorescence measurements, and group comparisons were performed using unpaired t-tests.

Following selective central dopamine denervation contractile responses to EFS and methacholine were significantly reduced compared to controls. In addition, relaxatory responses to noradrenaline were significantly impaired. Histological analyses revealed a marked downregulation of muscarinic M3 and adrenergic β3 receptors in bladder smooth muscle. In contrast, selective peripheral lesion in comparison with saline treatment showed no significant changes in contractile responses to EFS or methacholine, although a trend toward increased noradrenaline-induced relaxation was observed.

Central dopaminergic lesion was associated with pronounced functional and molecular alterations in the urinary bladder, affecting both contractile and relaxatory pathways. However, peripheral neurodegeneration alone resulted in more limited functional changes, suggesting that central mechanisms play a more prominent role in bladder dysfunction.

The current study suggests that urinary bladder dysfunction in PD is primarily driven by central mechanisms and is more consistent with the “brain-first” phenotype. This work contributes to a better understanding of the mechanisms underlying autonomic dysfunction in PD.

Continence 19S (2026) 102768
DOI: 10.1016/j.cont.2026.102768