Dual κ‐agonist/μ‐antagonist opioid receptor modulation reduces levodopa‐induced dyskinesia and corrects dysregulated striatal changes in the nonhuman primate model of Parkinson disease

Abstract

Objective: Effective medical management of L-dopa induced dyskinesia (LID) remains an unmet need for patients with Parkinson’s disease (PD). Changes in opioid transmission in the basal ganglia associated with LID suggest a therapeutic opportunity. Here we determined the impact of modulating both mu and kappa opioid receptor signaling using the mixed antagonist/agonist analgesic nalbuphine in reducing LID and its molecular markers in the non-human primate model. Methods: MPTP-treated macaques with advanced parkinsonism and reproducible LID received a range of nalbuphine doses or saline s.c. as: 1) monotherapy, 2) acute co-administration with L-dopa, and 3) chronic co-administration for a month. Animals were assessed by blinded examiners for motor disability and LID severity using standardized rating scales. Plasma L-dopa levels were determined with and without nalbuphine, and postmortem brain samples were subjected to Western blot analyses. Results: Nalbuphine reduced LID in a dose-dependent manner by 48% (p < 0.001) without compromising the anti-parkinson effect of L-dopa or changing plasma L-dopa levels. There was no tolerance to the anti-LID effect of nalbuphine given chronically. Nalbuphine co-administered with L-dopa was well tolerated and did not cause sedation. Nalbuphine monotherapy had no effect on motor disability. Striatal tissue analyses showed that nalbuphine co-therapy blocks several molecular correlates of LID including over-expression of ΔFosB, prodynorphin, dynorphin A, cyclin-dependent kinase 5 (Cdk5), and increased phosphorylation of DARPP-32 at Threonine34. Interpretation: Nalbuphine reverses the molecular milieu in the striatum associated with LID and is a safe and effective anti-LID agent in the primate model of PD. These findings support repurposing this analgesic for the treatment of LID.

Opioid K receptor variant is associated with a delayed onset of dyskinesias in Parkinson’s disease

“…In conclusion, the present data support prospective investigation on independent PD populations to elucidate the relationship between LIDs and opioid transmission, aiming to develop effective antidyskinetic strategies focused on KOP agonists(e-8) or mixed KOP agonists/μ-opioid peptide(MOP) antagonists5 …”

A Selective Phosphodiesterase 10A Inhibitor Reduces L‐Dopa‐Induced Dyskinesias in Parkinsonian Monkeys

“…The dose of MR1916 for the chronic trial was selected based on results in acute trials. Once every week during this 5‐week period, MR1916 was given with the suboptimal subcutaneous dose of l ‐dopa methyl ester instead of the oral l ‐dopa dose for assessment of reliable responses to subcutaneous l ‐dopa and accurate testing of sustained MR1916 effects or development of tolerance . Responses to the treatment combination MR1916 plus subcutaneous l ‐dopa methyl ester were compared across the following time points: baseline (day 0: subcutaneous l ‐dopa methyl ester plus MR1916 0 mg/kg); every week (weeks 1 through 5; subcutaneous l ‐dopa methyl ester plus MR1916 0.015 mg/kg); and 1 week after discontinuation of daily MR1916 as washout for a test of baseline recovery (day 42: subcutaneous l ‐dopa methyl ester plus MR1916 0 mg/kg; see also Supplemental Fig.…”

“…Motor evaluations were performed using a standardized primate motor scale (PMS) for MPTP‐treated monkeys (see the scale in Supplementary Information) . The PMS has two parts: motor disability is rated in Part I (which is similar to Part III of the UPDRS used for PD patients), and LIDs are rated in Part II .…”

“…Measurements of behavioral effects composed parametric data that were analyzed using one‐ or two‐way analysis of variance for repeated measures followed by Fisher's least significant difference test when the F indicated significance . Nonprocessed and normalized data (to control values) were used for analysis.…”

“…MR1916 was administered at doses of 0.005, 0.015, 0.05, and 0.15 mg/kg, subcutaneous alone or at 0.15 mg/kg, subcutaneous in combination with L-dopa methyl ester plus benserazide (25/6.25 mg/ kg, subcutaneous). Blood samples were collected at 15,30, 60, 120, 180, 240, and 480 minutes after drug administration and were processed in duplicates. Using aliquots of plasma samples, MR1916 and L-dopa with internal standards were extracted with a protein precipitation method and analyzed by liquid chromatography with tandem mass spectrometry.…”