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.