Flores Andrew J, Bartlett Mitchell J, Seaton Blake T, Samtani Grace, Sexauer Morgan R, Weintraub Nathan C, Siegenthaler James R, Lu Dong, Heien Michael L, Porreca Frank, Sherman Scott J, Falk Torsten
bioRxiv. 2023 Sep 26:2023.07.31.551112. doi: 10.1101/2023.07.31.551112.
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 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) with measuring tonic levels of striatal DA. Nor-BNI (3 mg/kg; s.c.) did not lead to functional restoration in the DA-depleted state, but a change in 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-hydroxydopamine (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 dosing with 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 saw an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI.
阿片肽强啡肽是一种对κ-阿片受体（KORs）具有选择性的内源性配体，其水平、mRNA及前体肽前体在帕金森病（PD）及左旋多巴诱导的异动症（LID）发生后存在不同程度的失调。目前尚不清楚这些改变是导致PD运动障碍及随后LID发生的病理生理机制的一部分，还是属于代偿机制的一部分。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的张力水平来进行研究。在中度纹状体6-羟基多巴胺（6-OHDA）损伤的大鼠PD模型中，nor-BNI（3mg/kg；皮下注射）在DA耗竭状态下未导致功能恢复，但随着L-DOPA剂量的增加，异常自主运动（AIMs）的剂量依赖性发展发生了变化。我们测试了五个递增剂量的L-DOPA（6、12、24、48、72mg/kg；腹腔注射），nor-BNI在12mg/kg和24mg/kg的L-DOPA剂量下显著增加了AIMs的发生。然而，在给予72mg/kg的L-DOPA后，对照组和nor-BNI组之间的AIMs没有显著差异。总之，在中度损伤的大鼠PD模型中，阻断KORs显著增加了慢性递增剂量L-DOPA诱导的LID的发展速度，但一旦LID的总体严重程度确定，它就不再起进一步作用。虽然我们在中度损伤的背外侧纹状体中看到了张力性DA水平的升高，但给予nor-BNI后张力性DA没有变化。
