Enhanced preproenkephalin-B-derived opioid transmission in striatum and subthalamic nucleus converges upon globus pallidus internalis in L-3,4-dihydroxyphenylalanine-induced dyskinesia.
BACKGROUND
A role for enhanced opioid peptide transmission has been suggested in the genesis of levodopa-induced dyskinesia. However, basal ganglia nuclei other than the striatum have not been regarded as potential sources, and the opioid precursors have never been quantified simultaneously with the levels of opioid receptors at the peak of dyskinesia severity.


METHODS
The levels of messenger RNA (mRNA) encoding the opioid precursors preproenkephalin-A and preproenkephalin-B in the striatum and the subthalamic nucleus and the levels of mu, delta, and kappa opioid receptors were measured within the basal ganglia of four groups of nonhuman primates killed at the peak of effect: normal, parkinsonian, parkinsonian chronically-treated with levodopa without exhibiting dyskinesia, and parkinsonian chronically-treated with levodopa showing overt dyskinesia.


RESULTS
Dyskinesia are associated with reduction in opioid receptor binding and specifically of kappa and mu receptor binding in the globus pallidus internalis (GPi), the main output structure of the basal ganglia. This decrease was correlated with enhancement of the expression of preproenkephalin-B mRNA but not that of preproenkephalin-A in the striatum and the subthalamic nucleus.


CONCLUSIONS
Abnormal transmission of preproenkephalin-B-derived opioid coming from the striatum and the subthalamic nucleus converges upon GPi at the peak of dose to induce levodopa-induced dyskinesia.
Aubert
Incarnation
I
Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 5541, Bordeaux Cedex, France.
Guigoni
Céline
C
Li
Qin
Q
Dovero
Sandra
S
Bioulac
Bernard H
BH
Gross
Christian E
CE
Crossman
Alan R
AR
Bloch
Bertrand
B
Bezard
Erwan
E
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects; D003342:Corpus Striatum / Q000378:metabolism*; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017403:In Situ Hybridization / Q000379:methods; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects; D008252:Macaca fascicularis; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay / Q000379:methods; D011957:Receptors, Opioid / Q000378:metabolism*; D012044:Regression Analysis; D020531:Subthalamic Nucleus / Q000378:metabolism*
D000978:Antiparkinson Agents; D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; D011957:Receptors, Opioid; D007980:Levodopa; C033660:preproenkephalin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine