Dyskinesias are observed in the majority of Parkinson's disease (PD) patients who have been chronically exposed to levodopa, and these may result from supersensitivity of postsynaptic striatal dopamine D1 and D2 receptors following loss of nigral dopaminergic projections. Dyskinetic and nondyskinetic PD patients were studied using 11C-SCH23390 and 11C-raclopride positron emission tomography (PET). No difference in mean putamen or caudate D1 or D2 receptor binding between the two patient subgroups was found, suggesting that dyskinesias are unlikely to arise from a primary disturbance of dopamine receptor availability. When dyskinetic and nondyskinetic patients were studied with 11C-diprenorphine PET, the former showed a significant reduction (p < 0.05) in striatal and thalamic opioid site availability, compatible with the presence of raised levels of endogenous opioid peptides. H2(15)O PET activation studies of patients with focal limb dyskinesias showed that resting levels of regional cerebral blood flow after oral levodopa were increased during dyskinesias in lentiform nuclei, motor, premotor and dorsal prefrontal cortex. These results suggest that dyskinesias are associated with derangement of basal ganglia opioid transmission, resulting in overactivity of basal ganglia-frontal projections.