TRK-820, a selective kappa opioid receptor agonist, could effectively ameliorate L-DOPA-induced dyskinesia symptoms in a rat model of Parkinson's disease.
Long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) in parkinsonian patients is known to lead to dyskinesia within a few years, and repeated administration of L-DOPA is also likely to alter the expression of kappa opioid receptors in the basal ganglia, especially the striatum and substantia nigra pars reticulata, suggesting that kappa opioid receptors might be deeply involved in motor functions. Therefore, effects of TRK-820 ((E)-N-[17-(cyclopropylmethyl)-4,5alpha-epoxy-3,14-dihydroxymorphinan-6beta-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride), a selective kappa opioid receptor agonist, were investigated on rotational behavior in unilateral 6-hydroxydopamine (6-OHDA)-treated rats (hemi-parkinsonian rats) and on L-DOPA-induced dyskinesia produced by administering L-DOPA to hemi-parkinsonian rats for 3 weeks (dyskinesia rats). A single administration of subcutaneous TRK-820 significantly increased spontaneous ipsilateral rotational behavior of hemi-parkinsonian rats at 30 microg/kg though the efficacy was moderate and also significantly inhibited L-DOPA-induced dyskinesia at 10 and 30 microg/kg; this inhibition was reversed in the presence of nor-binaltorphimine, a kappa opioid receptor antagonist. In vivo microdialysis study, TRK-820 (30 microg/kg, s.c.) significantly inhibited L-DOPA-derived extracellular dopamine content in the 6-OHDA-treated striatum in dyskinesia rats, but not in hemi-parkinsonian rats. Moreover, the development of L-DOPA-induced dyskinesia was suppressed by the 3-week co-administration of TRK-820 (3 and 10 microg/kg, s.c.) with L-DOPA. These results have suggested that TRK-820 ameliorates L-DOPA-induced dyskinesia with a moderate anti-parkinsonian effect by inhibiting L-DOPA-induced excessive dopamine release through kappa opioid receptors only in dyskinesia rats; therefore, TRK-820 is expected to become a useful agent for the treatment of L-DOPA-induced dyskinesia.
Ikeda
Ken
K
Toray Industries Inc, Pharmaceutical Research Laboratories, Kamakura, Kanagawa, Japan. Ken_Ikeda@nts.toray.co.jp
Yoshikawa
Satoru
S
Kurokawa
Takahiro
T
Yuzawa
Natsumi
N
Nakao
Kaoru
K
Mochizuki
Hidenori
H
D000547:Amantadine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D020820:Dyskinesias / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D017551:Microdialysis; D009019:Morphinans / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012399:Rotation; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
D009019:Morphinans; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820; D007980:Levodopa; D016627:Oxidopamine; D000547:Amantadine