MPTP treatment increases expression of pre-pro-nociceptin/orphanin FQ mRNA in a subset of substantia nigra reticulata neurons

Abstract Antagonists selectively inhibiting activation of the nociceptin/orphanin FQ (N/OFQ) receptor reduce motor symptoms in experimental models of Parkinson's disease, and genetic deletion of the ppN/OFQ gene offers partial protection of mid-brain dopamine neurons against the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP increased ppN/OFQ mRNA expression in the substantia nigra (SN). We have evaluated the temporal relationship of dopamine cell loss to increased ppN/OFQ mRNA expression in the substantia nigra after MPTP treatment, and characterized the cellular locations in which increased ppN/OFQ mRNA expression was observed after MPTP treatment. MPTP increased by about 5-fold the number of neurons expressing ppN/OFQ mRNA in the pars reticulata of SN (SNr) by 24 h after treatment and the elevation remained significant for at least 7 days. This period coincided with the timing of the loss of dopamine neurons from the pars compacta of substantia nigra (SNc) after MPTP. The increased expression of ppN/OFQ mRNA co-localized with a neuronal marker in the SNr. MPTP treatment resulted in a small increase in the numbers of neurons expressing ppN/OFQ in the SNc in mice from one mouse colony but the increase did not reach statistical significance in mice from another colony. No changes in ppN/OFQ-mRNA expression were observed in the ventral tegmental area (VTA), the caudate-putamen, the subthalamic nucleus, or in two other brains areas. These results demonstrate that increased N/OFQ expression in the SNr is closely associated with the MPTP-induced loss of dopamine neurons in the SNc in a widely used animal model of Parkinson's disease.