title: Blockade of nociceptin/orphanin FQ transmission attenuates symptoms and neurodegeneration associated with Parkinson's disease.
abstract: 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.
authors.affiliation: Department of Experimental and Clinical Medicine, Neuroscience Center, University of Ferrara, 44100 Ferrara, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Marti
authors.forename: Flora
authors.initials: F
authors.lastname: Mela
authors.forename: Martina
authors.initials: M
authors.lastname: Fantin
authors.forename: Silvia
authors.initials: S
authors.lastname: Zucchini
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Brown
authors.forename: Jassir
authors.initials: J
authors.lastname: Witta
authors.forename: Manuela
authors.initials: M
authors.lastname: Di Benedetto
authors.forename: Beata
authors.initials: B
authors.lastname: Buzas
authors.forename: Rainer K
authors.initials: RK
authors.lastname: Reinscheid
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Patrizia
authors.initials: P
authors.lastname: Romualdi
authors.forename: Sanzio
authors.initials: S
authors.lastname: Candeletti
authors.forename: Michele
authors.initials: M
authors.lastname: Simonato
authors.forename: Brian M
authors.initials: BM
authors.lastname: Cox
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
mesh_terms: 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
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007980:Levodopa; D018847:Opioid Peptides; D000097629:Nociceptin