Long-term treatment of
Parkinson's disease with
levodopa is compromised by the development of motor complications, including on-off fluctuations and
involuntary movements termed
dyskinesia. The neural mechanisms underlying treatment-related
dyskinesias may involve underactivity of the output regions of the basal ganglia, i.e., the medial segment of the globus pallidus (GPm) and substantia nigra pars reticulata (SNR). Increased activity of GABAergic neurons of the "direct" striatopallidal pathway has been implicated in the suppression of the GPm and SNR and thus the development of
dyskinesia. The direct pathway uses
opioids as a co-
neurotransmitter. These
opioid peptides are products of the high-molecular weight
opioid precursor
pre-proenkephalin B (PPE-B). In situ hybridisation studies were employed to investigate PPE-B
mRNA expression in postmortem striatal tissue from patients with a clinicopathological diagnosis of
Parkinson's disease, all of whom displayed
levodopa-induced motor complications, including
dyskinesia prior to death and in the caudate-putamen (striatum) of the
MPTP-lesioned macaque model of
Parkinson's disease with treatment-related
dyskinesia. Striatal PPE-B
mRNA expression was significantly increased by 172% in dyskinetic
Parkinson's disease patients compared to age-matched controls. This increase was heterogeneous with increased expression within the striosomes compared to matrix compartments of the striatum. Striatal PPE-B
mRNA expression was significantly increased by 185% in the
MPTP-lesioned macaque exhibiting
dyskinesia, compared to parkinsonian, nondyskinetic
MPTP-lesioned macaques, and by 146% compared to non-parkinsonian, nondyskinetic controls. Increased PPE-B
mRNA expression, with subsequent elevations in
opioid peptide transmission within the direct striatal output pathways, may underlie treatment-related
dyskinesia in
Parkinson's disease.