Expression and release of nociceptin/orphanin FQ (N/OFQ) are elevated in the substantia nigra reticulata of 6-hydroxydopamine hemilesioned rats, suggesting a pathogenic role for N/OFQ in Parkinson’s disease. In the present study we investigated whether elevation of N/OFQ expression in 6-hydroxydopamine hemilesioned rats selectively occurs in substantia nigra, and whether hypomotility following acute haloperidol administration is accompanied by a rise in nigral N/OFQ levels. Moreover, to prove a link between N/OFQ and idiopathic Parkinson’s disease in humans, we measured N/OFQ levels in the cerebrospinal fluid of parkinsonian patients undergoing surgery for deep brain stimulation. In situ hybridization demonstrated that dopamine depletion was associated with increase of N/OFQ expression in substantia nigra (compacta +160%, reticulata +105%) and subthalamic nucleus (+45%) as well as reduction in caudate putamen (-20%). No change was observed in globus pallidus, nucleus accumbens, thalamus and motor cortex. Microdialysis coupled to the bar test allowed to demonstrate that acute administration of haloperidol (0.8 and 3 mg/Kg) increased nigral N/OFQ levels (maximally of +47% and +53%, respectively) in parallel with akinesia. A correlation with preclinical studies was found by analysing N/OFQ levels in humans. Indeed, N/OFQ levels were found to be ~3.5-fold elevated in the cerebrospinal fluid of parkinsonian patients (148 fmol/ml) compared to non parkinsonian neurological controls (41 fmol/ml). These data represent the first clinical evidence linking N/OFQ to idiopathic Parkinson’s disease in humans. They strengthen the pathogenic role of N/OFQ in the modulation of parkinsonism across species and provide a rationale for developing N/OFQ receptor antagonists as antiparkinsonian drugs.
Brain interstitial nociceptin/orphanin FQ levels are elevated in Parkinson’s disease
MARTI, Matteo;SARUBBO, Silvio;CAVALLO, Michele Alessandro;ELEOPRA, Roberto;SIMONATO, Michele;ZUCCHINI, Silvia;QUATRALE, Rocco;SENSI, Mariachiara;MORARI, Michele
2010
Abstract
Expression and release of nociceptin/orphanin FQ (N/OFQ) are elevated in the substantia nigra reticulata of 6-hydroxydopamine hemilesioned rats, suggesting a pathogenic role for N/OFQ in Parkinson’s disease. In the present study we investigated whether elevation of N/OFQ expression in 6-hydroxydopamine hemilesioned rats selectively occurs in substantia nigra, and whether hypomotility following acute haloperidol administration is accompanied by a rise in nigral N/OFQ levels. Moreover, to prove a link between N/OFQ and idiopathic Parkinson’s disease in humans, we measured N/OFQ levels in the cerebrospinal fluid of parkinsonian patients undergoing surgery for deep brain stimulation. In situ hybridization demonstrated that dopamine depletion was associated with increase of N/OFQ expression in substantia nigra (compacta +160%, reticulata +105%) and subthalamic nucleus (+45%) as well as reduction in caudate putamen (-20%). No change was observed in globus pallidus, nucleus accumbens, thalamus and motor cortex. Microdialysis coupled to the bar test allowed to demonstrate that acute administration of haloperidol (0.8 and 3 mg/Kg) increased nigral N/OFQ levels (maximally of +47% and +53%, respectively) in parallel with akinesia. A correlation with preclinical studies was found by analysing N/OFQ levels in humans. Indeed, N/OFQ levels were found to be ~3.5-fold elevated in the cerebrospinal fluid of parkinsonian patients (148 fmol/ml) compared to non parkinsonian neurological controls (41 fmol/ml). These data represent the first clinical evidence linking N/OFQ to idiopathic Parkinson’s disease in humans. They strengthen the pathogenic role of N/OFQ in the modulation of parkinsonism across species and provide a rationale for developing N/OFQ receptor antagonists as antiparkinsonian drugs.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
