title: Enkephalin and dynorphin neuropeptides are differently correlated with locomotor hypersensitivity and levodopa-induced dyskinesia in parkinsonian rats.
abstract: The opioidergic neuropeptides dynorphin (DYN) and enkephalin (ENK) and the D1 and D2 dopaminergic receptors (D1R, D2R) are involved in the striatal control of motor and behavioral function. In Parkinson's disease, motor disturbances such as "on-off" motor fluctuations and involuntary movements (dyskinesia) are severe complications that often arise after chronic l-dihydroxyphenylalanine (l-DOPA) treatment. Changes in the striatal expression of preproENK (PPENK), proDYN (PDYN), D1R, and D2R mRNA have been observed in parkinsonian animals treated with l-DOPA. Enhanced opioidergic transmission has been found in association with l-DOPA-induced dyskinesia, but the connection of PPENK, PDYN, D1R, and D2R mRNA expression with locomotor activity remains unclear. In this study, we measured PPENK, PDYN, D1R and D2R mRNA levels by in situ hybridization in the striatum of 6-OHDA hemi-parkinsonian rats treated with l-DOPA (PD+l-DOPA group), along with two control groups (PD+saline and naive+l-DOPA). We found different levels of expression of PPENK, PDYN, D1R and D2R mRNA across the experimental groups and correlated the changes in mRNA expression with dyskinesia and locomotor variables assessed by open field test during several phases of l-DOPA treatment. Both PDYN and PPENK mRNA levels were correlated with the severity of dyskinesia, while PPENK mRNA levels were also correlated with the frequency of contralateral rotational movements and with locomotor variables. Moreover, a strong correlation was found between D1R mRNA expression and D2R mRNA expression in the PD+l-DOPA group. These findings suggest that, in parkinsonian animals treated with l-DOPA, high levels of PPENK are a prerequisite for a locomotor sensitization to l-DOPA treatment, while PDYN overexpression is responsible only for the development of dyskinesia.
authors.affiliation: Department of Neurology and Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3010 Bern, Switzerland; LBN - Laboratory for Biomedical Neurosciences, Neurocenter of Southern Switzerland, 6900 Lugano, Switzerland.
authors.forename: Stefania
authors.initials: S
authors.lastname: Sgroi
authors.affiliation: Department of Neurology and Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Capper-Loup
authors.affiliation: LBN - Laboratory for Biomedical Neurosciences, Neurocenter of Southern Switzerland, 6900 Lugano, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
authors.affiliation: LBN - Laboratory for Biomedical Neurosciences, Neurocenter of Southern Switzerland, 6900 Lugano, Switzerland. Electronic address: alain.kaelin@eoc.ch.
authors.forename: Alain
authors.initials: A
authors.lastname: Kaelin-Lang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000378:metabolism*; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007980:Levodopa / Q000009:adverse effects*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000235:genetics / Q000378:metabolism; D013223:Statistics as Topic; D013565:Sympatholytics / Q000633:toxicity; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D013565:Sympatholytics; D007980:Levodopa; D004399:Dynorphins; D016627:Oxidopamine; C033660:preproenkephalin; D014446:Tyrosine 3-Monooxygenase
keywords: Circling behavior; Dopaminergic receptors; Dyskinesia; Locomotor hyperactivity; Opioidergic neuropeptides; l-DOPA; mRNA expression