The novel nociceptin/orphanin FQ receptor antagonist Trap-101 alleviates experimental parkinsonism through inhibition of the nigro-thalamic pathway: positive interaction with L-DOPA.
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.
Marti
Matteo
M
Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
Trapella
Claudio
C
Morari
Michele
M
D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000378:metabolism; D007839:Functional Laterality / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D007980:Levodopa / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009292:Narcotic Antagonists; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000172:deficiency; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology*; D013788:Thalamus / Q000187:drug effects / Q000503:physiopathology*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000094942:Nociceptin Receptor
C539677:1-(1-(cyclooctylmethyl)-1,2,3,6-tetrahydro-5-(hydroxymethyl)-4-pyridinyl)-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; D000978:Antiparkinson Agents; D001562:Benzimidazoles; D009292:Narcotic Antagonists; D011725:Pyridines; D011957:Receptors, Opioid; D018698:Glutamic Acid; D007980:Levodopa; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; D000094942:Nociceptin Receptor