Ropinirole versus l-DOPA effects on striatal opioid peptide precursors in a rodent model of Parkinson's disease: implications for dyskinesia

Abstract

The dopamine precursor, l-3,4-dihydroxyphenylalanine ( l-DOPA), remains the most common treatment for Parkinson's disease. However, following long-term treatment, disabling side effects, particularly l-DOPA-induced dyskinesias, are encountered. Conversely, D 2/D 3 dopamine receptor agonists, such as ropinirole, exert an anti-parkinsonian effect while eliciting less dyskinesia when administered de novo in Parkinson's disease patients. Parkinson's disease and l-DOPA-induced dyskinesia are both associated with changes in mRNA and peptide levels of the opioid peptide precursors preproenkephalin-A (PPE-A) and preproenkephalin-B (PPE-B). Furthermore, a potential role of abnormal opioid peptide transmission in dyskinesia is suggested due to the ability of opioid receptor antagonists to reduce the l-DOPA-induced dyskinesia in animal models of Parkinson's disease. In this study, the behavioural response, striatal topography and levels of expression of the opioid peptide precursors PPE-A and PPE-B were assessed, following repeated vehicle, ropinirole, or l-DOPA administration in the 6-OHDA-lesioned rat model of Parkinson's disease. While repeated administration of l-DOPA significantly elevated PPE-B mRNA levels (313% cf. vehicle, 6-OHDA-lesioned rostral striatum; 189% cf. vehicle, 6-OHDA-lesioned caudal striatum) in the unilaterally 6-OHDA-lesioned rat model of Parkinson's disease, ropinirole did not. These data and previous studies suggest the involvement of enhanced opioid transmission in l-DOPA-induced dyskinesia and that part of the reason why D 2/D 3 dopamine receptor agonists have a reduced propensity to elicit dyskinesia may reside in their reduced ability to elevate opioid transmission.