Brain Interstitial Nociceptin/Orphanin FQ Levels are Elevated in Parkinson's Disease |
| |
Authors: | Matteo Marti PhD Silvio Sarubbo MD Francesco Latini MD Michele Cavallo MD Roberto Eleopra MD Sara Biguzzi MD Christian Lettieri MD Carlo Conti MD Michele Simonato MD Silvia Zucchini PhD Rocco Quatrale MD Mariachiara Sensi MD Sanzio Candeletti PhD Patrizia Romualdi PhD Michele Morari PhD |
| |
Institution: | 1. Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy;2. Center for Neuroscience and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy;3. Division of Neurosurgery, S. Anna University Hospital of Ferrara, Ferrara, Italy;4. Clinical and Neurological Department, Angel's Hospital of Mestre, Venice, Italy;5. Department of Neurosurgery, Angel's Hospital of Mestre, Venice, Italy;6. Clinical and Neurological Department, S. Anna University Hospital of Ferrara, Ferrara, Italy;7. Department of Pharmacology, University of Bologna, Bologna, Italy |
| |
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 this 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 analyzing 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 with nonparkinsonian neurologic 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. © 2010 Movement Disorder Society |
| |
Keywords: | cerebrospinal fluid haloperidol human nociceptin/orphanin FQ 6‐OHDA Parkinson's disease |
|
|