Alterations of N/OFQ and NOP receptor gene expression in the substantia nigra and caudate putamen of MPP+ and 6-OHDA lesioned rats.
It has been suggested that the opioid-like neuropeptide nociceptin/orphanin FQ(N/OFQ) and its receptor (NOPr) may contribute to Parkinson's disease. Based on this idea, the aim of our study was to investigate the involvement of the N/OFQ-NOPr system in an animal model of Parkinson's disease and to evaluate if this neuropeptidergic system is acting through mechanisms involving glutamate and/or GABA. We injected the neurotoxins MPP+ or 6-OHDA into the cerebral ventricles and 10 days later measured N/OFQ and NOPr gene expression in caudate putamen (CP) and substantia nigra (SN), by RT-PCR. A large reduction in N/OFQ and NOPr mRNAs was observed in the CP of rat treated with either MPP+ or 6-OHDA, MPP+ being more effective than 6-OHDA. Both the neurotoxins induced an increase in N/OFQ gene expression in the SN, but only MPP+ evoked a significant down-regulation of NOPr in this area, showing a slight trend of reduction in 6-OHDA treated rats. Moreover, a reduction in the levels of glutamic acid decarboxylase (GAD65/67), an enzyme that converts the excitatory neurotransmitter glutamate to the inhibitory neurotransmitter y-aminobutyric acid (GABA), was also observed in the SN following 6-OHDA. These data suggest that DA modulates N/OFQ-NOPr system gene expression in SN and CP, strengthening the hypothesis that this neuropeptidergic system could be implicated in the mechanisms underlying Parkinson's disease. Our data might also suggest that the GABAergic system plays a role in the regulation of nigral function, although further studies are necessary to confirm this hypothesis. In agreement with previous studies, we also support the hypothesis of a potential value for NOP receptor antagonists to attenuate symptoms related to the degeneration of nigrostriatal dopaminergic pathway.
Di Benedetto
Manuela
M
Department of Pharmacology, Alma Mater Studiorum-University of Bologna, Imerio 48, 40126 Bologna, Italy.
Cavina
Chiara
C
D'Addario
Claudio
C
Leoni
Giorgia
G
Candeletti
Sanzio
S
Cox
Brian M
BM
Romualdi
Patrizia
P
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002421:Caudate Nucleus / Q000378:metabolism*; D015870:Gene Expression; D005968:Glutamate Decarboxylase / Q000378:metabolism; D020267:MPTP Poisoning / Q000473:pathology*; D008297:Male; D018847:Opioid Peptides / Q000235:genetics*; D016627:Oxidopamine / Q000633:toxicity*; D011699:Putamen / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000378:metabolism*; D013565:Sympatholytics / Q000633:toxicity*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D015655:1-Methyl-4-phenylpyridinium; D005968:Glutamate Decarboxylase; D018847:Opioid Peptides; D016627:Oxidopamine; D012313:RNA; D011957:Receptors, Opioid; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000722285:Oprl1 protein, rat