Elsevier

Biological Psychiatry

Volume 61, Issue 7, 1 April 2007, Pages 836-844
Biological Psychiatry

Original Article
Enhanced Preproenkephalin-B–Derived Opioid Transmission in Striatum and Subthalamic Nucleus Converges Upon Globus Pallidus Internalis in L-3,4-dihydroxyphenylalanine–Induced Dyskinesia

https://doi.org/10.1016/j.biopsych.2006.06.038Get rights and content

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 μ, δ, and κ 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 κ and μ 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.

Section snippets

Animals

Seventeen female cynomolgus monkeys (Macaca fascicularis, SAH, Beijing, China) were used for this study. Animals were housed in individual primate cages under controlled conditions of humidity (50% ± 5%), temperature (24 ± 1°C), and light (12-hour light/dark cycles, lights on at 8:00 am); food and water were available ad libitum, and animal care was supervised by veterinarians skilled in the health care and maintenance of nonhuman primates. Experiments were carried out in accordance with

Total Opioid Binding Sites

The MPTP lesion and L-dopa treatment did significantly affect the [3H] diprenorphine binding (Figure 2A) in the putamen [for example in the caudal putamen; treatment effect: F(3,63) = 4.19, p = .01; but no quadrant effect: F(3,63) = .39, p = .76 nor interaction: F(9,63) = .06, p = .99] and in the GPi, the main output structure of basal ganglia [F(3,15) = 3.74, p = .04] but not in the caudate nucleus [caudal caudate: F(3,15) = 2.57, p = .1] or in the GPe [F(3,15) = 2.93, p = .08]. Although post

Discussion

The MPTP-lesioned monkey model of PD has been used to show that, at the peak of L-dopa effect, abnormal transmission of PPE-B–derived opioid coming from the striatum and the STN converges upon GPi concomitantly with LID expression. Enhanced transmission is ascertained by the concomitant increased striatal and subthalamic PPE-B mRNA levels and the decrease in total opioid, μ, and κ receptor binding in GPi.

Confirmation was obtained that DA-denervation induces a significant upregulation of PPE-A

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