Alterations in descending brain-spinal pathways regulating colorectal motility in a rat model of Parkinson's disease.

Patients with Parkinson's disease (PD) often have constipation. It is assumed that a disorder of the regulatory mechanism of colorectal motility by the central nervous system is involved in the constipation, but this remains unclear. The aim of this study was to investigate whether central neural pathways can modulate colorectal motility in a rat model of PD. PD model rats were generated by injection of 6-hydroxydopamine into a unilateral medial forebrain bundle and destruction of dopaminergic neurons in the substantia nigra. Colorectal motility was measured in vivo in anesthetized rats. Intraluminal administration of capsaicin, as a noxious stimulus, induced colorectal motility in sham-operated rats but not in PD rats. Intrathecally administered dopamine (DA) and serotonin (5-HT), which mediate the prokinetic effect of capsaicin, at the L6-S1 levels enhanced colorectal motility in PD rats similarly to that in sham-operated rats. In PD rats, capsaicin enhanced colorectal motility only when a GABA receptor antagonist was preadministered into the lumbosacral spinal cord. Capsaicin-induced colorectal motility was abolished by intrathecal administration of a D2-like receptor antagonist but not by administration of 5-HT and 5-HT receptor antagonists. These findings demonstrate that the inhibitory GABAergic component becomes operative and the stimulatory serotonergic component is suppressed in PD rats. The alteration of the central regulatory mechanism of colorectal motility is thought to be related to the occurrence of constipation in PD patients. Our findings provide a new insight into the pathogenesis of defecation disorders observed in PD. In a rat model of Parkinson's disease, the component of descending brain-spinal pathways that regulate colorectal motility through a mediation of the lumbosacral defecation center was altered from stimulatory serotonergic neurons to inhibitory GABAergic neurons. Our findings suggest that chronic constipation in Parkinson's disease patients may be associated with alterations in central regulatory mechanisms of colorectal motility. The plasticity in the descending pathway regulating colorectal motility may contribute to other disease-related defecation abnormalities.