µ Opioid Receptor Agonism for L-DOPA-Induced Dyskinesia in Parkinson's Disease

Abstract

Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine precursor L-DOPA, but its prolonged usage causes dyskinesias referred to as L-DOPA-induced dyskinesia (LID). Several studies in animal models of PD have suggested that dyskinesias are associated with a heightened opioid cotransmitter tone, observations that have led to the notion of a LID-related hyperactive opioid transmission that should be corrected by m opioid receptor antagonists. Reports that both antagonists and agonists of the m opioid receptor may alleviate LID severity in primate models of PD and LID, together with the failure of nonspecific antagonist to improve LID in pilot clinical trials in patients, raises doubt about the reliability of the available data on the opioid system in PD and LID. After in vitro characterization of the functional activity at the m opioid receptor, we selected prototypical agonists, antagonists, and partial agonists at the m opioid receptor. We then showed that both oral and discrete intracerebral administration of a m receptor agonist, but not of an antagonist as long thought, ameliorated LIDs in the gold-standard bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinelesioned female macaque model of PD and LID. The results call for a reappraisal of opioid pharmacology in the basal ganglia as well as for the development of brain nucleus-targeted m opioid receptor agonists.

The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia

“…This is perhaps due to action at multiple sites that includes DOR activity. Consistent with the lack of effect of pure MOR antagonists, is the study of ADC-02265510, a MOR agonist which has shown anti-dyskinetic activity [9]. It is further interesting that sub-anesthetic ketamine treatment has recently been shown to be anti-dyskinetic and anti-Parkinsonian in rodent models [48,49].…”

“…In addition, the mixed KOR agonist/MOR antagonist nalbuphine was shown to reduce LID in dyskinetic non-human LID primates [45]. Blockade of the MOR receptor alone, with two highly-selective MOR antagonists, ADC-02520849 and CTAP, did not reduce LID [9,46], while a MOR antagonist with a very low selectivity, ADL5510, was successful in reducing LID [47]. This is perhaps due to action at multiple sites that includes DOR activity.…”

“…The initial condition of PD and the subsequent development of LID are both associated with alterations in mRNA and peptide levels of these opioid precursors [1,3]. Thus, the regulation of opioid peptides within the basal ganglia is closely associated with the regulation of DA transmission [4][5][6][7], however, the role played by altered opioid transmission in PD (compensatory vs. pathological) has not been resolved [1,8,9]. In response to DA depletion, striatal PPE-A mRNA and enkephalin peptide levels are upregulated [5,[10][11][12][13], while striatal PPE-B mRNA and dynorphin are downregulated [5,[12][13][14][15].…”

Current Knowledge on the Background, Pathophysiology, and Treatment of Levodopa-Induced Dyskinesia – Literature Review.

“…The significant results of this experiment may be due to the dualistic nature of the treatment strategy used -highly selective μ-opioid receptor antagonism did not improve dyskinesia in the tested 6-OHDA rats [135]. Only μ receptor agonists appeared to reduce the incidence of LID when used alone [136].…”

Exome-wide association study of levodopa-induced dyskinesia in Parkinson’s disease

“…The direction of effect in our data (Supplementary Table S2 ) suggests that carriers of the G allele have shorter time-to-LID onset, and that therefore differential sensitivity of the mu opioid receptor to endogenous opioids could play a role in time-to-LID onset. By extension, agonists of the mu opioid receptor might be therapeutic in slowing LID onset, and can provide anti-dyskinetic benefit as has been recently discussed 13 .…”