Nociceptin/orphanin FQ (N/OFQ) is an opioid-like neuropeptide discovered in the mid 90's, which activates a G-protein coupled receptor, the NOP receptor. N/OFQ and its receptor are diffusely expressed in the mammalian brain, being involved in the modulation of several functions such as pain transmission, mood, reward, cognition and locomotion. By employing a genetic and pharmacological approach, we recently demonstrated that endogenous N/OFQ inhibits the nigrostriatal transmission and motor behavior in rats through activation of NOP receptors expressed onto dopaminergic neurons of the substantia nigra (SN) compacta. Our preliminary work in pre-clinical models of Parkinson's disease also indicates that endogenous N/OFQ sustains parkinsonism. Indeed, pharmacological blockade of N/OFQ transmission by NOP receptor antagonists facilitated motor performance of hemiparkinsonian rats (i.e. rats made parkinsonian via unilateral injection of 6-hydroxydopamine) and attenuated akinesia and catalepsy induced by systemic haloperidol injection. On the basis of these findings we provided the novel concept that blockade of N/OFQ transmission may represent a novel approach for Symptoms & Side Effects therapy of Parkinson's disease. To investigate this, we plan experiments in mice and primates rendered parkinsonian with MPTP. This will extend previous observations made in rats and possibly confirm the pathogenetic role of N/OFQ among species. The present project will provide novel information on the behavioral profile of a systemically active NOP receptor antagonist in pre-clinical models and definitely will tell us whether NOP receptor antagonists have to be regarded as potential new drugs for management of parkinsonism in humans.