Effects of the novel glycopeptide opioid agonist MMP-2200 in preclinical models of Parkinson's disease

Xu Yue, Torsten Falk, Leslie A. Zuniga, Lajos Szabò, Frank Porreca, Robin L Polt, Scott J Sherman

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

In Parkinson's disease (PD), the consequence of dopaminergic denervation is an imbalance in the activity of the direct and indirect striatofugal pathways, which include potentially important changes in opioid peptide expression and/or activity. The systemic administration of a novel glycosylated opioid peptide MMP-2200 (a.k.a. lactomorphin) was shown to have potent effects in two standard models of PD: 1) amphetamine-induced rotations in the hemi-Parkinsonian 6-hydroxydopamine (6-OHDA)-treated rat and 2) locomotion in the reserpine-treated rat. MMP-2200, an opioid mu and delta receptor agonist, reduced amphetamine-induced rotations in severely-lesioned hemi-Parkinsonian rats; this effect was fully blocked by naloxone, an opioid receptor antagonist. The selective δ-opioid receptor antagonist naltrindole only partially blocked the effect of MMP-2200. MMP-2200 alone did not induce rotations. This effect was also observed in a mild progressive rat 6-OHDA-lesion model. In animals treated with reserpine, profound akinesia was induced that was reversed with apomorphine. There was a prominent overshoot in animals that received apomorphine compared to non-reserpine treated animals, reflecting the well described phenomenon of dopamine supersensitivity indicating that apomorphine not only reversed akinesia but also induced hyper-kinesia. The opioid peptide MMP-2200 blocked the apomorphine-induced hyper-kinesia. This effect of MMP-2200 was prevented by pre-administration of naloxone. MMP-2200 had no effect in preventing the reserpine-induced akinesia, nor did it affect locomotion in control animals. Taken together, the results from these two models are consistent with the glycopeptide opioid agonist MMP-2200 having a potent effect on movements related to dopaminergic hyper-stimulation following striatal dopamine depletion that are best explained by a reduction in the downstream effects of dopamine agonists in these models.

Original languageEnglish (US)
Pages (from-to)72-83
Number of pages12
JournalBrain Research
Volume1413
DOIs
StatePublished - Sep 21 2011

Fingerprint

Glycopeptides
Opioid Analgesics
Parkinson Disease
Apomorphine
Opioid Peptides
Oxidopamine
Reserpine
naltrindole
Narcotic Antagonists
Amphetamine
Locomotion
Dopamine
Corpus Striatum
delta Opioid Receptor
tyrosyl-glycyl-phenylalanyl-leucyl-(O-lactosyl)serinamide
mu Opioid Receptor
Dopamine Agonists
Denervation
Naloxone

Keywords

  • δ-Opioid receptor
  • μ-Opioid receptor
  • 6-OHDA
  • Akinesia
  • Dopaminergic hyper-stimulation
  • Reserpine

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

Effects of the novel glycopeptide opioid agonist MMP-2200 in preclinical models of Parkinson's disease. / Yue, Xu; Falk, Torsten; Zuniga, Leslie A.; Szabò, Lajos; Porreca, Frank; Polt, Robin L; Sherman, Scott J.

In: Brain Research, Vol. 1413, 21.09.2011, p. 72-83.

Research output: Contribution to journalArticle

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