MPTP treatment increases expression of pre-pro-nociceptin/orphanin FQ mRNA in a subset of substantia nigra reticulata neurons.
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.
Gouty
S
S
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Brown
J M
JM
Rosenberger
J
J
Cox
B M
BM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D020267:MPTP Poisoning / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D018847:Opioid Peptides / Q000096:biosynthesis / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics*; D011498:Protein Precursors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D011957:Receptors, Opioid / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism; D000097629:Nociceptin
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D018847:Opioid Peptides; D011498:Protein Precursors; D012333:RNA, Messenger; D011957:Receptors, Opioid; D000097629:Nociceptin; C121527:prepronociceptin