title: Nociceptin/Orphanin FQ Inhibits the Survival and Axon Growth of Midbrain Dopaminergic Neurons Through a p38-MAPK Dependent Mechanism.
abstract: Nociceptin/orphanin FQ (N/OFQ) is an opioid-like neuropeptide that binds and signals through a G-protein-coupled receptor called the N/OFQ peptide (NOP) receptor. N/OFQ and the NOP receptor are expressed in the midbrain and have been implicated in the pathogenesis of Parkinson's disease (PD). Genetic removal of the N/OFQ precursor partially protects midbrain dopaminergic neurons from 1-methyl-4-phenylpyridine-induced toxicity, suggesting that endogenous N/OFQ may be detrimental to dopaminergic neurons. However, whether N/OFQ directly affects the survival and growth of dopaminergic neurons is unknown. Here, we show that N/OFQ has a detrimental effect on the survival of dopaminergic neurons and the growth of their axons in primary cultures of the E14 rat ventral mesencephalon. N/OFQ potentiates the effects of the neurotoxins 6-hydroxydopamine and 1-methyl-4-phenylpyridinium through p38-MAPK signalling. We also show that like α-synuclein, there is a significant reduction in N/OFQ messenger RNA (mRNA) expression in the midbrain of patients with Parkinson's disease. These results demonstrate for the first time that N/OFQ is detrimental to the survival and growth of dopaminergic neurons and that its expression is altered in the midbrain of patients with Parkinson's disease.
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Collins
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.|Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Dal Bo
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Calcagno
authors.affiliation: School of Life Sciences, University of Lincoln, Lincoln, Lincolnshire, LN6 7TS, UK.|Department of Biology and Biochemistry, University of Bath, Bath, UK.
authors.forename: Jimena
authors.initials: J
authors.lastname: Monzón-Sandoval
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
authors.forename: Aideen M
authors.initials: AM
authors.lastname: Sullivan
authors.affiliation: School of Life Sciences, University of Lincoln, Lincoln, Lincolnshire, LN6 7TS, UK.
authors.forename: Humberto
authors.initials: H
authors.lastname: Gutierrez
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy. m.morari@unife.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. g.okeeffe@ucc.ie.
authors.forename: Gerard W
authors.initials: GW
authors.lastname: O'Keeffe
mesh_terms: D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008636:Mesencephalon / Q000166:cytology*; D009498:Neurotoxins / Q000633:toxicity; D018847:Opioid Peptides / Q000494:pharmacology*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000097629:Nociceptin
chemical_list: D015655:1-Methyl-4-phenylpyridinium; D009498:Neurotoxins; D018847:Opioid Peptides; D016627:Oxidopamine; D012333:RNA, Messenger; D051844:alpha-Synuclein; D048051:p38 Mitogen-Activated Protein Kinases; D000097629:Nociceptin
keywords: Axon; Dopaminergic; Growth; Human; Neuron; Nociceptin/orphanin FQ; Parkinson’s disease; Survival; p38-MAPK