Title

 

Authors

F. Blandini², M. Colucci¹, M. Cervio¹, G. Levandis², B. Balestra¹,C. Tassorelli², O. Pastoris¹, G. Nappi², R. De Giorgio³, M. Tonini¹†

¹Department of Legal Medicine, Forensic Sciences and Pharmaco-Toxicology, University of Pavia, Pavia, Italy;²IRCCS National Neurological Institute C. Mondino Foundation, Pavia; ³Departmentof Clinical Medicine, University of Bologna, Bologna, Italy
†deceased April 29th, 2010

 

Abstract

Gastrointestinal disorders, constipation in particular, are the most common non-motor dysfunctions affecting patients with Parkinson’s disease (PD). We have previously reported that rats bearing a nigrostriatal lesion caused by 6-hydroxydopamine (6-OHDA) stereotaxic injection - which reproduces the central dopaminergic denervation typical of PD - develop severe constipation and region-specific phenotypic changes of enteric neurons, represented by a decrease of nitric oxide synthase (nNOS) immunoreactivity (IR) in the lower intestinal tract (distal ileum and proximal colon). Here, we sought to extend these observations by investigating the effects of central dopaminergic denervation on other enteric neuronal subpopulations, as well as on the peristaltic activity of isolated colonic segments. We observed, twenty-eight days after 6-OHDA injection, a significant increase of vasoactive intestinal polypeptide (VIP)-IR concomitant with the reduced expression of nNOS-IR in the myenteric plexus of the distal ileum and proximal colon of lesioned compared to intact animals; co-expression analysis revealed a significant increase of VIP-IR in a subpopulation of neurons actively expressing nNOS. On the other hand, choline acetyltransferase (ChAT)-IR was not modified following 6-OHDA injection, in any of the intestinal segments analyzed. We also found a strong reduction in the expression of dopamine D2 receptors in the proximal (-62%) and distal (-66%) colon of lesioned animals. Functional experiments conducted on isolated distal colon segments revealed a general alteration of peristaltic activity, which developed with a different motility pattern in the 6-OHDA lesioned rats compared to controls. In particular, pressure parameters and frequency of the single peristaltic events were decreased, with a multi-spike trend, corresponding to a multi-zone peristaltic initiation, which substituted the normal motility pattern observed in intact animals.  In conclusion, our results show that a selective lesion of dopaminergic nigrostriatal neurons is associated with changes in the expression of enteric inhibitory neurotransmitters and dopaminergic receptors, which translate into an impairment of the peristalsis efficiency. These changes may reflect the enteric neuronal impairment underlying the chronic constipation that frequently affects PD patients.