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- Title
The novel nociceptin/orphanin FQ receptor antagonist Trap-101 alleviates experimental parkinsonism through inhibition of the nigro-thalamic pathway: positive interaction withL-DOPA.
- Authors
Marti, Matteo; Trapella, Claudio; Morari, Michele
- 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 μM), 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 ofl-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.
- Subjects
OPIOID receptors; MICRODIALYSIS; DOPA; LABORATORY rats; GABA; NEUROTRANSMITTERS
- Publication
Journal of Neurochemistry, 2008, Vol 107, Issue 6, p1683
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2008.05735.x