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

Neuroscience. 2009 Dec 1;164(2):360-9. doi: 10.1016/j.neuroscience.2009.08.058. Epub 2009 Sep 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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