diprenorphine and Dyskinesia--Drug-Induced

Opioid receptor-binding autoradiography was used as a way to map sites of altered opioid transmission in a rat model of l-DOPA-induced dyskinesia. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathways sustained a 3-week treatment with l-DOPA (6 mg/kg/day, combined with 12 mg/kg/day benserazide), causing about half of them to develop dyskinetic-like movements on the side of the body contralateral to the lesion. Autoradiographic analysis of mu-, delta-, and kappa-opioid binding sites was carried out in the caudate-putamen (CPu), the globus pallidus (GP), the substantia nigra (SN), the primary motor area, and the premotor-cingulate cortex. The dopamine-denervating lesion alone caused an ipsilateral reduction in opioid radioligand binding in the CPu, GP, and SN, but not in the cerebral cortex. Chronic l-DOPA treatment affected opioid receptor binding in both the basal ganglia and the cerebral cortex, producing changes that were both structure- and receptor-type specific, and closely related to the motor response elicited by the treatment. In the basal ganglia, the most clear-cut differences between dyskinetic and nondyskinetic rats pertained to kappa opioid sites. On the lesioned side, both striatal and nigral levels of kappa binding densities were significantly lower in the dyskinetic group, showing a negative correlation with the rats' dyskinesia scores on one hand and with the striatal expression of opioid precursor mRNAs on the other hand. In the cerebral cortex, levels of mu and delta binding site densities were bilaterally elevated in the dyskinetic group, whereas kappa radioligand binding was specifically increased in the nondyskinetic cases and showed a negative correlation with the rats' dyskinesia scores. These data demonstrate that bilateral changes in cortical opioid transmission are closely associated with l-DOPA-induced dyskinesia in the rat. Moreover, the fact that dyskinetic and nondyskinetic animals often show opposite changes in opioid radioligand binding suggests that the motor response to l-DOPA is determined, at least in part, by compensatory adjustments of brain opioid receptors.

Topics: Animals; Basal Ganglia; Behavior, Animal; Binding Sites; Cerebral Cortex; Diprenorphine; Disease Models, Animal; Dopamine Agents; Dyskinesia, Drug-Induced; Enkephalins; Female; Levodopa; Narcotic Antagonists; Oxidopamine; Protein Precursors; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; RNA, Messenger; Sympatholytics; Tritium

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