Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA; Graduate Interdisciplinary Program in Physiological Sciences, The University of Arizona, Tucson, AZ 85724, USA.
Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA; Department of Pharmacology, The University of Arizona, Tucson, AZ 85724, USA.
Brain Res. 2023 Dec 15;1821:148613. doi: 10.1016/j.brainres.2023.148613. Epub 2023 Sep 30.
Levels of the opioid peptide dynorphin, an endogenous ligand selective for kappa-opioid receptors (KORs), its mRNA and pro-peptide precursors are differentially dysregulated in Parkinson's disease (PD) and following the development of l-DOPA-induced dyskinesia (LID). It remains unclear whether these alterations contribute to the pathophysiological mechanisms underlying PD motor impairment and the subsequent development of LID, or whether they are part of compensatory mechanisms. We sought to investigate nor-BNI, a KOR antagonist, 1) in the dopamine (DA)-depleted PD state, 2) during the development phase of LID, and 3) via measuring of tonic levels of striatal DA. While nor-BNI (3 mg/kg; s.c.) did not lead to functional restoration in the DA-depleted state, it affected the dose-dependent development of abnormal voluntary movements (AIMs) in response to escalating doses of l-DOPA in a rat PD model with a moderate striatal 6-hydroxdopamine (6-OHDA) lesion. We tested five escalating doses of l-DOPA (6, 12, 24, 48, 72 mg/kg; i.p.), and nor-BNI significantly increased the development of AIMs at the 12 and 24 mg/kg l-DOPA doses. However, after reaching the 72 mg/kg l-DOPA, AIMs were not significantly different between control and nor-BNI groups. In summary, while blocking KORs significantly increased the rate of development of LID induced by chronic, escalating doses of l-DOPA in a moderate-lesioned rat PD model, it did not contribute further once the overall severity of LID was established. While we observed an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI.
内源性阿片肽强啡肽的水平，一种对κ-阿片受体（KOR）有选择性的内源性配体，其 mRNA 和前肽前体在帕金森病（PD）和左旋多巴诱导的运动障碍（LID）发展后出现不同程度的失调。目前尚不清楚这些改变是否有助于 PD 运动障碍的病理生理机制以及随后 LID 的发展，或者它们是否是代偿机制的一部分。我们试图研究 KOR 拮抗剂 nor-BNI，1）在多巴胺（DA）耗竭的 PD 状态下，2）在 LID 的发展阶段，以及 3）通过测量纹状体 DA 的紧张水平。虽然 nor-BNI（3mg/kg；sc）在 DA 耗竭状态下没有导致功能恢复，但它影响了在中度纹状体 6-羟多巴胺（6-OHDA）损伤的大鼠 PD 模型中，对递增剂量的 l-DOPA 反应的异常自主运动（AIMs）的剂量依赖性发展。我们测试了五个递增剂量的 l-DOPA（6、12、24、48、72mg/kg；ip），nor-BNI 显著增加了 12 和 24mg/kg l-DOPA 剂量的 AIMs 发展。然而，在达到 72mg/kg l-DOPA 后，对照组和 nor-BNI 组之间的 AIMs 没有显著差异。总之，虽然阻断 KORs 显著增加了慢性、递增剂量的 l-DOPA 在中度损伤的大鼠 PD 模型中诱导的 LID 的发展速度，但在 LID 的总体严重程度确立后，它并没有进一步增加。虽然我们观察到中度损伤的背外侧纹状体中的紧张性 DA 水平增加，但 nor-BNI 给药后没有紧张性 DA 变化。
