Brain interstitial nociceptin/orphanin FQ levels are elevated in Parkinson's disease

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-hy- droxydopamine-hemilesioned rats selectively occurs in sub- stantia nigra and whether hypomotility following acute halo- peridol 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 hybrid- ization demonstrated that dopamine depletion was associated with increase of N/OFQ expression in substantia nigra (com- pacta 1160%, reticulata 1105%) and subthalamic nucleus (145%), as well as reduction in caudate putamen (220%). No change was observed in globus pallidus, nucleus accum- bens, 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 lev- els (maximally of 147% and 153%, 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 cerebrospi- nal 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