The novel nociceptin/orphanin FQ receptor antagonist Trap-101 alleviates experimental parkinsonism through inhibition of the nigro-thalamic pathway: positive interaction with L-DOPA.

Abstract

In this study we investigated whether the recently discovered antagonist of the nociceptin/orphanin FQ (N/OFQ) opioid peptide (NOP) receptor, 1-[1-(cyclooctylmethyl)-1,2,3,6-tetrahydro-5-(hydroxymethyl)-4-pyridinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (Trap-101) changed motor activity in naïve rats and mice, and alleviated parkinsonism in 6-hydroxydopamine hemilesioned rats. In naïve rats, Trap-101 stimulated motor activity at 10 mg/Kg and inhibited it at 30 mg/Kg. Such dual action was also observed in wild-type but not NOP receptor knockout mice suggesting specific involvement of NOP receptors. Trap-101 alleviated akinesia/bradykinesia and improved overall gait ability in hemiparkinsonian rats, being effective starting at 1 mg/Kg and without worsening motor deficit at 30 mg/Kg. To investigate the circuitry involved in the Trap-101 action, behavioral tests were performed in rats undergoing microdialysis. The anti-akinetic/anti-bradykinetic effects of Trap-101, given systemically (10 mg/Kg) or perfused in substantia nigra reticulata (10 microM), were associated with reduced glutamate and enhanced GABA release in substantia nigra, and reduced GABA release in ipsilateral ventro-medial thalamus. When combined with ineffective doses of l-DOPA (0.1 mg/Kg), Trap-101 evoked larger neurochemical and behavioral responses. These data show that Trap-101 is an effective NOP receptor antagonist in vivo and confirm that NOP receptor antagonists alleviate parkinsonism through blockade of nigral NOP receptors and impairment of nigro-thalamic transmission.

• Authors: Matteo Marti, Claudio Trapella, Michele Morari
• Journal: Journal of neurochemistry (J Neurochem) Vol. 107 Issue 6 Pg. 1683-96 (Dec 2008) ISSN: 1471-4159 [Electronic] England
• PMID: 19014386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(1-(cyclooctylmethyl)-1,2,3,6-tetrahydro-5-(hydroxymethyl)-4-pyridinyl)-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one
• Antiparkinson Agents
• Benzimidazoles
• Narcotic Antagonists
• Pyridines
• Receptors, Opioid
• Glutamic Acid
• Levodopa
• gamma-Aminobutyric Acid
• Oxidopamine
• Nociceptin Receptor

Topics

• Animals
• Antiparkinson Agents (therapeutic use)
• Benzimidazoles (pharmacology, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Interactions
• Dyskinesia, Drug-Induced (drug therapy, metabolism)
• Functional Laterality (drug effects)
• Glutamic Acid (metabolism)
• Levodopa (therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microdialysis (methods)
• Motor Activity (drug effects, physiology)
• Narcotic Antagonists
• Neural Pathways (drug effects, physiopathology)
• Oxidopamine
• Parkinsonian Disorders (chemically induced, drug therapy, pathology, physiopathology)
• Psychomotor Performance (drug effects, physiology)
• Pyridines (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid (deficiency)
• Substantia Nigra (drug effects, physiopathology)
• Thalamus (drug effects, physiopathology)
• Time Factors
• gamma-Aminobutyric Acid (metabolism)
• Nociceptin Receptor