Effects of the novel glycopeptide opioid agonist MMP-2200 in preclinical models of Parkinson's disease.
Effects of the novel glycopeptide opioid agonist MMP-2200 in preclinical models of Parkinson's disease.
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DOI：
10.1016/j.brainres.2011.07.038
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发表时间：
2011-09-21
期刊：
影响因子：
2.9
通讯作者：
Sherman SJ
中科院分区：
文献类型：
--
作者：
Yue X;Falk T;Zuniga LA;Szabò L;Porreca F;Polt R;Sherman SJ
在帕金森病（PD）中，多巴胺能去神经支配的后果是直接和间接离纹状体通路的活性失衡，其包括阿片肽表达和/或活性的潜在重要变化。全身施用新型糖基化阿片肽MMP-2200（a.k.a.乳啡肽）在两种标准PD模型中显示出有效的作用：1）在偏侧帕金森病6-羟基多巴胺（6-OHDA）处理的大鼠中安非他明诱导的旋转和2）在利血平处理的大鼠中的运动。MMP-2200，阿片样物质μ和δ受体激动剂，减少安非他明诱导的旋转在martely-lesioned偏侧帕金森病大鼠，这种作用完全阻断纳洛酮，阿片样物质受体拮抗剂。选择性δ阿片受体拮抗剂纳曲吲哚仅部分阻断MMP-2200的作用。单独的MMP-2200不诱导旋转。在轻度进行性大鼠6-OHDA损伤模型中也观察到该效应。在利血平治疗的动物中，诱导了深刻的运动不能，阿扑吗啡可以逆转。与非利血平处理的动物相比，接受阿扑吗啡的动物中存在显著的过冲，反映了充分描述的多巴胺超敏现象，表明阿扑吗啡不仅逆转了运动不能，而且诱导了运动过度。阿片肽MMP-2200阻断阿扑吗啡诱导的运动过度。MMP-2200的这种作用可通过预先给药纳洛酮来预防。MMP-2200对预防利血平诱导的运动不能没有作用，也不影响对照动物的运动。总之，这两种模型的结果与糖肽类阿片激动剂MMP-2200对纹状体多巴胺耗竭后与多巴胺能过度刺激相关的运动具有强效作用一致，这最好通过这些模型中多巴胺激动剂下游作用的减少来解释。
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 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.
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DOI：
10.1124/jpet.104.069393
发表时间：
2004-10-01
影响因子：
3.5
作者：
Elmagbari, NO;Egleton, RD;Bilsky, EJ
通讯作者：
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影响因子：
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影响因子：
5
作者：
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影响因子：
7.3
作者：
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影响因子：
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作者：
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