Ropinirole versus L-DOPA effects on striatal opioid peptide precursors in a rodent model of Parkinson's disease: implications for dyskinesia.
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.
Ravenscroft
Paula
P
School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK. paularavenscroft@motac.com
Chalon
Sylvie
S
Brotchie
Jonathan M
JM
Crossman
Alan R
AR
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000627:therapeutic use; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology* / Q000517:prevention & control; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017403:In Situ Hybridization; D007211:Indoles / Q000627:therapeutic use*; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018847:Opioid Peptides / Q000235:genetics / Q000378:metabolism*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D004745:Enkephalins; D007211:Indoles; D018847:Opioid Peptides; D011498:Protein Precursors; D012333:RNA, Messenger; C046649:ropinirole; D007980:Levodopa; D016627:Oxidopamine; C033660:preproenkephalin