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, D2/D3 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 D2/D3 dopamine receptor agonists have a reduced propensity to elicit dyskinesia may reside in their reduced ability to elevate opioid transmission.

• Authors: Paula Ravenscroft, Sylvie Chalon, Jonathan M Brotchie, Alan R Crossman
• Journal: Experimental neurology (Exp Neurol) Vol. 185 Issue 1 Pg. 36-46 (Jan 2004) ISSN: 0014-4886 [Print] United States
• PMID: 14697317 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• Dopamine Agonists
• Enkephalins
• Indoles
• Opioid Peptides
• Protein Precursors
• RNA, Messenger
• ropinirole
• Levodopa
• Oxidopamine
• preproenkephalin

Topics

• Animals
• Antiparkinson Agents (adverse effects, therapeutic use)
• Behavior, Animal (drug effects)
• Corpus Striatum (drug effects, metabolism, pathology)
• Disease Models, Animal
• Dopamine Agonists (therapeutic use)
• Dyskinesia, Drug-Induced (physiopathology, prevention & control)
• Enkephalins (genetics, metabolism)
• Gene Expression (drug effects)
• In Situ Hybridization
• Indoles (therapeutic use)
• Levodopa (adverse effects, therapeutic use)
• Male
• Motor Activity (drug effects)
• Opioid Peptides (genetics, metabolism)
• Oxidopamine
• Parkinsonian Disorders (chemically induced, drug therapy, pathology)
• Protein Precursors (genetics, metabolism)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Synaptic Transmission (drug effects)