title: Effects of the novel glycopeptide opioid agonist MMP-2200 in preclinical models of Parkinson's disease.
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.
authors.affiliation: College of Medicine, Department of Neurology, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Yue
authors.forename: Torsten
authors.initials: T
authors.lastname: Falk
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Zuniga
authors.forename: Lajos
authors.initials: L
authors.lastname: Szabò
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Robin
authors.initials: R
authors.lastname: Polt
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Sherman
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D006020:Glycopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000502:physiology
chemical_list: D006020:Glycopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C531935:tyrosyl-glycyl-phenylalanyl-leucyl-(O-lactosyl)serinamide