The combination of the opioid glycopeptide MMP-2200 and a NMDA receptor antagonist reduced L-DOPA-induced dyskinesia and MMP-2200 by itself reduced dopamine receptor 2-like agonist-induced dyskinesia

Andrew J. Flores, Mitchell J. Bartlett, Brandon K. Root, Kate L. Parent, Michael L Heien, Frank Porreca, Robin L Polt, Scott J Sherman, Torsten Falk

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Abstract

Dopamine (DA)-replacement therapy utilizing L-DOPA is the gold standard symptomatic treatment for Parkinson's disease (PD). A critical complication of this therapy is the development of L-DOPA-induced dyskinesia (LID). The endogenous opioid peptides, including enkephalins and dynorphin, are co-transmitters of dopaminergic, GABAergic, and glutamatergic transmission in the direct and indirect striatal output pathways disrupted in PD, and alterations in expression levels of these peptides and their precursors have been implicated in LID genesis and expression. We have previously shown that the opioid glycopeptide drug MMP-2200 (a.k.a. Lactomorphin), a glycosylated derivative of Leu-enkephalin mediates potent behavioral effects in two rodent models of striatal DA depletion. In this study, the mixed mu-delta agonist MMP-2200 was investigated in standard preclinical rodent models of PD and of LID to evaluate its effects on abnormal involuntary movements (AIMs). MMP-2200 showed antiparkinsonian activity, while increasing L-DOPA-induced limb, axial, and oral (LAO) AIMs by ∼10%, and had no effect on dopamine receptor 1 (D1R)-induced LAO AIMs. In contrast, it markedly reduced dopamine receptor 2 (D2R)-like-induced LAO AIMs. The locomotor AIMs were reduced by MMP-2200 in all three conditions. The N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 has previously been shown to be anti-dyskinetic, but only at doses that induce parkinsonism. When MMP-2200 was co-administered with MK-801, MK-801-induced pro-parkinsonian activity was suppressed, while a robust anti-dyskinetic effect remained. In summary, the opioid glycopeptide MMP-2200 reduced AIMs induced by a D2R-like agonist, and MMP-2200 modified the effect of MK-801 to result in a potent reduction of L-DOPA-induced AIMs without induction of parkinsonism.

Original languageEnglish (US)
Pages (from-to)260-271
Number of pages12
JournalNeuropharmacology
Volume141
DOIs
StatePublished - Oct 1 2018

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Glycopeptides
Dyskinesias
Dopamine Receptors
N-Methyl-D-Aspartate Receptors
Opioid Analgesics
Dizocilpine Maleate
Corpus Striatum
tyrosyl-glycyl-phenylalanyl-leucyl-(O-lactosyl)serinamide
Extremities
Parkinsonian Disorders
Parkinson Disease
Rodentia
Dopamine
Secondary Parkinson Disease
Antiparkinson Agents
Leucine Enkephalin
Dynorphins
Opioid Peptides
Enkephalins

Keywords

  • 6-Hydroxydopamine
  • L-DOPA-induced dyskinesia
  • NMDA receptor antagonist
  • Opioid glycopeptide
  • δ-Opioid receptor (DOR)
  • μ-Opioid receptor (MOR)

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

@article{eccc52e818734e6a89ac7f35c4a55726,
title = "The combination of the opioid glycopeptide MMP-2200 and a NMDA receptor antagonist reduced L-DOPA-induced dyskinesia and MMP-2200 by itself reduced dopamine receptor 2-like agonist-induced dyskinesia",
abstract = "Dopamine (DA)-replacement therapy utilizing L-DOPA is the gold standard symptomatic treatment for Parkinson's disease (PD). A critical complication of this therapy is the development of L-DOPA-induced dyskinesia (LID). The endogenous opioid peptides, including enkephalins and dynorphin, are co-transmitters of dopaminergic, GABAergic, and glutamatergic transmission in the direct and indirect striatal output pathways disrupted in PD, and alterations in expression levels of these peptides and their precursors have been implicated in LID genesis and expression. We have previously shown that the opioid glycopeptide drug MMP-2200 (a.k.a. Lactomorphin), a glycosylated derivative of Leu-enkephalin mediates potent behavioral effects in two rodent models of striatal DA depletion. In this study, the mixed mu-delta agonist MMP-2200 was investigated in standard preclinical rodent models of PD and of LID to evaluate its effects on abnormal involuntary movements (AIMs). MMP-2200 showed antiparkinsonian activity, while increasing L-DOPA-induced limb, axial, and oral (LAO) AIMs by ∼10{\%}, and had no effect on dopamine receptor 1 (D1R)-induced LAO AIMs. In contrast, it markedly reduced dopamine receptor 2 (D2R)-like-induced LAO AIMs. The locomotor AIMs were reduced by MMP-2200 in all three conditions. The N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 has previously been shown to be anti-dyskinetic, but only at doses that induce parkinsonism. When MMP-2200 was co-administered with MK-801, MK-801-induced pro-parkinsonian activity was suppressed, while a robust anti-dyskinetic effect remained. In summary, the opioid glycopeptide MMP-2200 reduced AIMs induced by a D2R-like agonist, and MMP-2200 modified the effect of MK-801 to result in a potent reduction of L-DOPA-induced AIMs without induction of parkinsonism.",
keywords = "6-Hydroxydopamine, L-DOPA-induced dyskinesia, NMDA receptor antagonist, Opioid glycopeptide, δ-Opioid receptor (DOR), μ-Opioid receptor (MOR)",
author = "Flores, {Andrew J.} and Bartlett, {Mitchell J.} and Root, {Brandon K.} and Parent, {Kate L.} and Heien, {Michael L} and Frank Porreca and Polt, {Robin L} and Sherman, {Scott J} and Torsten Falk",
year = "2018",
month = "10",
day = "1",
doi = "10.1016/j.neuropharm.2018.09.005",
language = "English (US)",
volume = "141",
pages = "260--271",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - The combination of the opioid glycopeptide MMP-2200 and a NMDA receptor antagonist reduced L-DOPA-induced dyskinesia and MMP-2200 by itself reduced dopamine receptor 2-like agonist-induced dyskinesia

AU - Flores, Andrew J.

AU - Bartlett, Mitchell J.

AU - Root, Brandon K.

AU - Parent, Kate L.

AU - Heien, Michael L

AU - Porreca, Frank

AU - Polt, Robin L

AU - Sherman, Scott J

AU - Falk, Torsten

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Dopamine (DA)-replacement therapy utilizing L-DOPA is the gold standard symptomatic treatment for Parkinson's disease (PD). A critical complication of this therapy is the development of L-DOPA-induced dyskinesia (LID). The endogenous opioid peptides, including enkephalins and dynorphin, are co-transmitters of dopaminergic, GABAergic, and glutamatergic transmission in the direct and indirect striatal output pathways disrupted in PD, and alterations in expression levels of these peptides and their precursors have been implicated in LID genesis and expression. We have previously shown that the opioid glycopeptide drug MMP-2200 (a.k.a. Lactomorphin), a glycosylated derivative of Leu-enkephalin mediates potent behavioral effects in two rodent models of striatal DA depletion. In this study, the mixed mu-delta agonist MMP-2200 was investigated in standard preclinical rodent models of PD and of LID to evaluate its effects on abnormal involuntary movements (AIMs). MMP-2200 showed antiparkinsonian activity, while increasing L-DOPA-induced limb, axial, and oral (LAO) AIMs by ∼10%, and had no effect on dopamine receptor 1 (D1R)-induced LAO AIMs. In contrast, it markedly reduced dopamine receptor 2 (D2R)-like-induced LAO AIMs. The locomotor AIMs were reduced by MMP-2200 in all three conditions. The N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 has previously been shown to be anti-dyskinetic, but only at doses that induce parkinsonism. When MMP-2200 was co-administered with MK-801, MK-801-induced pro-parkinsonian activity was suppressed, while a robust anti-dyskinetic effect remained. In summary, the opioid glycopeptide MMP-2200 reduced AIMs induced by a D2R-like agonist, and MMP-2200 modified the effect of MK-801 to result in a potent reduction of L-DOPA-induced AIMs without induction of parkinsonism.

AB - Dopamine (DA)-replacement therapy utilizing L-DOPA is the gold standard symptomatic treatment for Parkinson's disease (PD). A critical complication of this therapy is the development of L-DOPA-induced dyskinesia (LID). The endogenous opioid peptides, including enkephalins and dynorphin, are co-transmitters of dopaminergic, GABAergic, and glutamatergic transmission in the direct and indirect striatal output pathways disrupted in PD, and alterations in expression levels of these peptides and their precursors have been implicated in LID genesis and expression. We have previously shown that the opioid glycopeptide drug MMP-2200 (a.k.a. Lactomorphin), a glycosylated derivative of Leu-enkephalin mediates potent behavioral effects in two rodent models of striatal DA depletion. In this study, the mixed mu-delta agonist MMP-2200 was investigated in standard preclinical rodent models of PD and of LID to evaluate its effects on abnormal involuntary movements (AIMs). MMP-2200 showed antiparkinsonian activity, while increasing L-DOPA-induced limb, axial, and oral (LAO) AIMs by ∼10%, and had no effect on dopamine receptor 1 (D1R)-induced LAO AIMs. In contrast, it markedly reduced dopamine receptor 2 (D2R)-like-induced LAO AIMs. The locomotor AIMs were reduced by MMP-2200 in all three conditions. The N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 has previously been shown to be anti-dyskinetic, but only at doses that induce parkinsonism. When MMP-2200 was co-administered with MK-801, MK-801-induced pro-parkinsonian activity was suppressed, while a robust anti-dyskinetic effect remained. In summary, the opioid glycopeptide MMP-2200 reduced AIMs induced by a D2R-like agonist, and MMP-2200 modified the effect of MK-801 to result in a potent reduction of L-DOPA-induced AIMs without induction of parkinsonism.

KW - 6-Hydroxydopamine

KW - L-DOPA-induced dyskinesia

KW - NMDA receptor antagonist

KW - Opioid glycopeptide

KW - δ-Opioid receptor (DOR)

KW - μ-Opioid receptor (MOR)

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U2 - 10.1016/j.neuropharm.2018.09.005

DO - 10.1016/j.neuropharm.2018.09.005

M3 - Article

C2 - 30201210

AN - SCOPUS:85054375353

VL - 141

SP - 260

EP - 271

JO - Neuropharmacology

JF - Neuropharmacology

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