The novel delta opioid receptor agonist UFP-512 dually modulates motor activity in hemiparkinsonian rats via control of the nigro-thalamic pathway.

Abstract

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.

• Authors: O S Mabrouk, M Marti, S Salvadori, M Morari
• Journal: Neuroscience (Neuroscience) Vol. 164 Issue 2 Pg. 360-9 (Dec 01 2009) ISSN: 1873-7544 [Electronic] United States
• PMID: 19729051 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1H-benzimidazol-2-yl)(carboxymethyl)methylamide
• Amino Acids
• Antiparkinson Agents
• Benzimidazoles
• Narcotic Antagonists
• Oligopeptides
• Receptors, Opioid, delta
• Glutamic Acid
• gamma-Aminobutyric Acid
• Naltrexone
• Oxidopamine
• naltrindole

Topics

• Amino Acids (metabolism)
• Animals
• Antiparkinson Agents (administration & dosage, pharmacology)
• Benzimidazoles (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Globus Pallidus (drug effects, metabolism)
• Glutamic Acid (metabolism)
• Male
• Motor Activity (drug effects)
• Naltrexone (analogs & derivatives, pharmacology)
• Narcotic Antagonists (pharmacology)
• Neural Pathways (drug effects, metabolism)
• Oligopeptides (administration & dosage, pharmacology)
• Oxidopamine
• Parkinsonian Disorders (chemically induced, drug therapy, metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid, delta (agonists, antagonists & inhibitors)
• Substantia Nigra (drug effects, metabolism)
• Thalamus (drug effects, metabolism)
• gamma-Aminobutyric Acid (metabolism)