Solving a major complication of Parkinson’s disease: targeting debilitating constipation through novel pharmacology

Chronic constipation affects up to 90% of Parkinson’s disease (PD) patients, significantly impacting their quality of life. While the motor deficits of PD are attributed to nigro-striatal dopaminergic neuronal loss, the involvement of dopamine neurons of defecation pathways in the constipation phenotype remains unclear. We’ve found that dopamine causes excitation at the normally inhibitory dopamine 2 (D2) receptors in the lumbo-sacral defecation centre, this reversal of effect being due to ghrelin receptor mediated modulation of D2 receptors.

Our study also builds on the discovery that centrally penetrant ghrelin receptor agonists, when administered systemically or orally, induce defecation in both laboratory animals and humans. Notably, ghrelin receptor agonists that cross the blood-brain barrier, unlike ghrelin itself, trigger defecation by acting on lumbo-sacral spinal cord centres when given peripherally. These spinal defecation centres are vital in coordinating colonic, rectal, and pelvic floor muscle activity for normal bowel function.

In this project, we are using a combination of neurotoxin-induced mouse model of PD and viral transfection methods to identify neural pathways that are responsible for defecation and are affected in PD. We’re trying to broaden our understanding of the intricate relationships between stress, ghrelin signalling, spinal defecation centres pathways, and gastrointestinal function in healthy and diseased states.