naltrindole and Parkinsonian-Disorders

The present study aimed to characterize the ability of the novel delta opioid peptide (DOP) receptor agonist H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512) to attenuate motor deficits in 6-hydroxydopamine (6-OHDA) hemilesioned rats. Lower doses (0.1-10 microg/kg) of UFP-512 administered systemically (i.p.) stimulated stepping activity in the drag test and overall gait abilities in the rotarod test whereas higher doses (100-1000 microg/kg) were ineffective or even worsened Parkinsonism. Microdialysis coupled to an akinesia test (bar test) was then used to determine the circuitry involved in the motor actions of UFP-512. An antiakinetic dose of UFP-512 (10 microg/kg) decreased GABA in globus pallidus (GP) as well as GABA and glutamate (GLU) release in substantia nigra reticulata (SNr). On the other hand, a pro-akinetic dose (1000 microg/kg) of UFP-512 increased pallidal GABA, simultaneously producing a decrease in GABA and an increase in nigral GLU release. Moreover, to test the hypothesis that changes in motor behavior were associated with changes in nigro-thalamic transmission, amino acid release in ventromedial thalamus (VMTh, a target of nigro-thalamic GABAergic projections) was also measured. The anti-akinetic dose of UFP-512 reduced GABA and increased thalamic GLU release while the pro-akinetic dose increased GABA without affecting thalamic GLU release. Finally, regional microinjections were performed to investigate the brain areas involved in motor actions of UFP-512. UFP-512 microinjections into GP increased akinesia whereas UFP-512 microinjections into SNr reduced akinesia. Furthermore, the selective DOP receptor antagonist naltrindole (NTD) increased akinesia when injected into either area, GP being more sensitive. We conclude that UFP-512, depending on dose, improves or worsens motor activity in hemiparkinsonian rats by acting differentially as a DOP receptor agonist in SNr and a DOP receptor antagonist in GP, ultimately decreasing or increasing the activity of nigro-thalamic GABAergc output neurons, respectively.

Topics: Amino Acids; Animals; Antiparkinson Agents; Benzimidazoles; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Globus Pallidus; Glutamic Acid; Male; Motor Activity; Naltrexone; Narcotic Antagonists; Neural Pathways; Oligopeptides; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Substantia Nigra; Thalamus

Long-term treatment of Parkinson's disease with levodopa is complicated by the emergence of involuntary movements, known as levodopa-induced dyskinesia. It has been hypothesized that increased opioid transmission in striatal output pathways may be responsible for the generation of dyskinesia. In this study, we have investigated the effect of blockade of opioid peptide transmission on levodopa-induced dyskinesia in a primate model of Parkinson's disease-the MPTP-lesioned marmoset. Coadministration of nonselective and mu- or delta-subtype-selective opioid receptor antagonists with levodopa resulted in a significant decrease in dyskinesia. There was no attenuation of the anti-parkinsonian actions of levodopa. These data suggest that specific mu- or delta-opioid receptor antagonists might be applicable clinically in the treatment of levodopa-induced dyskinesia in Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Callithrix; Disease Models, Animal; Drug Therapy, Combination; Dyskinesias; Female; Hypokinesia; Levodopa; Male; Morphinans; Motor Activity; Naltrexone; Narcotic Antagonists; Parkinsonian Disorders; Posture; Receptors, Opioid, delta; Receptors, Opioid, mu