diprenorphine and Parkinson-Disease

Levodopa-induced dyskinesias remain a major challenge in the therapeutic management of Parkinson's disease (PD). Their etiology is unknown although dysfunction of striatal opioid transmission has been implicated in experimental models of PD. To determine whether the opioid system is involved in human dyskinetic PD, we measured in vivo opioid receptor binding in PD patients with and without levodopa-induced dyskinesias, using positron emission tomography (PET) and the opioid receptor ligand [11C]diprenorphine. Striatal and thalamic/occipital uptake ratios were calculated using a region of interest (ROI) approach. In addition, we used statistical parametric mapping (SPM) and images reflecting the volume of distribution of [11C]diprenorphine to assess changes in cerebral receptor binding on a voxel-by-voxel basis. By using the ROI approach, we found significantly reduced striatal and thalamic opioid binding in dyskinetic, but not in nondyskinetic, PD patients. The SPM approach confirmed reduced availability in these areas and, in addition, showed decreased cingulate and increased prefrontal opioid receptor binding in the dyskinetic patients. Our findings confirm that altered opioid transmission is part of the pathophysiology of levodopa-induced dyskinesias in PD and support further investigation into the role of opioid agents in the management of these involuntary movements.

Topics: Adult; Aged; Antiparkinson Agents; Binding, Competitive; Brain Chemistry; Brain Mapping; Carbon Radioisotopes; Caudate Nucleus; Diprenorphine; Dyskinesia, Drug-Induced; Female; Humans; Levodopa; Magnetic Resonance Imaging; Male; Middle Aged; Narcotic Antagonists; Occipital Lobe; Parkinson Disease; Putamen; Receptors, Opioid; Thalamic Nuclei

The clinical differentiation of Parkinson's disease from the striatonigral degeneration (SND) type of multiple system atrophy (MSA) and Steele-Richardson-Olszewski syndrome (SRO) may be difficult. This is reflected by a 20-25% misdiagnosis rate in clinicopathological series of cases labelled as 'Parkinson's disease' in life. The caudate and putamen contain a high density of opioidergic neurons and receptors which have a close anatomical and physiological relationship with the dopaminergic system. We used [11C]diprenorphine with PET to investigate striatal opioid receptor binding in groups of patients with clinically defined Parkinson's disease (n = 8), SND (n = 7) and SRO (n = 6), compared with normal controls (n = 8). There was no significant difference between mean ligand binding in the putamen and caudate of Parkinson's disease cases when compared with normals. Mean putamen, but not caudate, opioid receptor binding was significantly reduced in the SND group, when compared with normals. By contrast, in the SRO group, both mean caudate and putamen opioid receptor binding was significantly reduced when compared with both normal and Parkinson's disease groups. When considering the individual patients, none of the eight Parkinson's disease cases (0%), none of the seven SND cases (0%), but four of the six SRO cases (67%) had caudate opioid receptor binding that was > 2.5 SDs below the normal mean. Corresponding figures for putamen opioid receptor binding were: none of the Parkinson's disease cases (0%); three of the SND cases (43%); and all of the SRO cases (100%). We conclude that there are differences in the pattern of opioid receptor binding in the striatum of Parkinson's disease, SND and SRO patients, as determined by [11C]diprenorphine PET. The different binding patterns may help to differentiate these akinetic-rigid syndromes in life.

Topics: Adult; Aged; Brain Diseases; Carbon Radioisotopes; Corpus Striatum; Diprenorphine; Female; Humans; Male; Middle Aged; Parkinson Disease; Receptors, Opioid; Substantia Nigra; Supranuclear Palsy, Progressive; Tomography, Emission-Computed