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Nociceptin/Orphanin FQ Inhibits the Survival and Axon Growth of Midbrain Dopaminergic Neurons Through a p38-MAPK Dependent Mechanism

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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.

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Acknowledgements

The authors acknowledge Dr. Sean Crampton for the technical assistance. This work was supported by grant support from Science Foundation Ireland (Grant No. :10/RFP/NES2786) (GO’K).

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Authors and Affiliations

  1. Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland

    Louise M. Collins, Giorgia Dal Bo, Aideen M. Sullivan & Gerard W. O’Keeffe

  2. Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy

    Giorgia Dal Bo, Mariangela Calcagno & Michele Morari

  3. School of Life Sciences, University of Lincoln, Lincoln, Lincolnshire, LN6 7TS, UK

    Jimena Monzón-Sandoval & Humberto Gutierrez

  4. Department of Biology and Biochemistry, University of Bath, Bath, UK

    Jimena Monzón-Sandoval

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  1. Louise M. Collins
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Collins, L.M., Dal Bo, G., Calcagno, M. et al. Nociceptin/Orphanin FQ Inhibits the Survival and Axon Growth of Midbrain Dopaminergic Neurons Through a p38-MAPK Dependent Mechanism. Mol Neurobiol 53, 7284–7297 (2016). https://doi.org/10.1007/s12035-015-9611-6

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