Blockade of nociceptin/orphanin FQ transmission attenuates symptoms and neurodegeneration associated with Parkinson's disease.
The opioid-like neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are expressed in the substantia nigra (SN), a brain area containing dopamine neurons that degenerate in Parkinson's disease. Endogenous N/OFQ facilitates nigral glutamate release and inhibits nigrostriatal dopamine transmission and motor behavior. Here, we present evidence suggesting that endogenous N/OFQ may contribute to Parkinson's disease. Pharmacological blockade of the SN N/OFQ-NOP receptor system attenuated parkinsonian-like akinesia/hypokinesia in 6-hydroxydopamine hemilesioned or haloperidol-treated rats, whereas deletion of the NOP receptor gene conferred mice partial protection from haloperidol-induced motor depression. The antiparkinsonian action of NOP receptor antagonists was associated with reduction of glutamate release in the SN. In 6-hydroxydopamine hemilesioned rats, enhancement of N/OFQ expression and release was detected in the lesioned compared with the unlesioned SN, indicating that parkinsonism may be associated with overactivation of the N/OFQ-NOP receptor system in the SN. Finally, deletion of the N/OFQ gene conferred mice partial protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of SN dopamine neurons. Based on these data, we propose that NOP receptor antagonists may represent a novel approach for combined (symptomatic and neuroprotective) therapy of Parkinson's disease.
Marti
Matteo
M
Department of Experimental and Clinical Medicine, Neuroscience Center, University of Ferrara, 44100 Ferrara, Italy.
Mela
Flora
F
Fantin
Martina
M
Zucchini
Silvia
S
Brown
Jeffrey M
JM
Witta
Jassir
J
Di Benedetto
Manuela
M
Buzas
Beata
B
Reinscheid
Rainer K
RK
Salvadori
Severo
S
Guerrini
Remo
R
Romualdi
Patrizia
P
Candeletti
Sanzio
S
Simonato
Michele
M
Cox
Brian M
BM
Morari
Michele
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology*; D018847:Opioid Peptides / Q000037:antagonists & inhibitors* / Q000502:physiology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D000097629:Nociceptin
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007980:Levodopa; D018847:Opioid Peptides; D000097629:Nociceptin