Dopamine receptor D3 agonist (Pramipexole) reduces morphine-induced cardiac fibrosis
Dopamine receptor D3 agonist (Pramipexole) reduces morphine-induced cardiac fibrosis
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DOI：
10.1016/j.bbrc.2020.06.137
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发表时间：
2020-09-03
影响因子：
3.1
通讯作者：
Bras, Lisandra E. de Castro
中科院分区：
文献类型：
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作者：
Gaweda, Gabriel;Iyer, Rugmani P.;Bras, Lisandra E. de Castro
吗啡通常用于治疗心力衰竭患者的疼痛。然而，延长吗啡暴露与主要不良心血管事件相关。报告将多巴胺受体 D2 家族与吗啡诱导的伤害感受调节联系起来。本研究首先评估吗啡是否会诱导健康小鼠的心脏重塑，然后评估 DRD3 激动剂（DRD3ag，D2 家族成员）辅助治疗是否可以预防吗啡诱导的心脏重塑。小鼠接受吗啡（2 mg/kg/天，腹膜内注射）7天（D7），并在D7处安乐死，或者在没有吗啡的情况下再保持7天（即戒断期，D8-D14）：G1，吗啡； G2，吗啡/DRD3ag； G3，吗啡+戒断； G4，吗啡/DRD3ag+戒断； G5，吗啡+戒断/DRD3ag。一组单独的动物被用作原始组织。我们评估了心脏重塑的功能和分子参数。尽管我们没有观察到收缩功能的显着差异，但吗啡诱导间质纤维化和心肌细胞肥大。有趣的是，DRD3ag 消除了这些影响。与初始组织相比，G3和G4中撤药后胶原蛋白1增加，G1-G4中胶原蛋白3增加，但G1和G2中水平更高。与初始相比，只有 G5 没有表现出胶原蛋白差异，这表明戒断期间的 DRD3ag 治疗可能是有益的，可以预防吗啡诱导的纤维化。 Smad2/3 磷酸化在戒断期间增加，表明观察到的吗啡诱导的纤维化可能是上游途径。总体而言，我们的数据表明 DRD3ag 辅助治疗可减少吗啡诱导的不良心脏重塑。 (C) 2020 Elsevier Inc. 保留所有权利。
Morphine is routinely used for pain management in heart failure patients. However, extended morphine exposure associates with major adverse cardiovascular events. Reports link the dopamine receptor D2 -family with morphine-induced nociception modulation. This study first assessed whether morphine induces cardiac remodeling in healthy mice, then whether DRD3 agonist (DRD3ag, D2-family member) adjunct therapy prevents morphine-induced cardiac remodeling. Mice received morphine (2 mg/kg/day i. p.) for 7 days (D7) and were either euthanized at D7 or kept 7 more days without morphine (i.e. withdrawal period, D8-D14): G1, morphine; G2, morphine/DRD3ag; G3, morphine + withdrawal; G4, morphine/DRD3ag + withdrawal; G5, morphine + withdrawal/DRD3ag. A separate cohort of animals were used as naive tissues. We evaluated functional and molecular parameters of cardiac remodeling. Although we did not observe significant differences in systolic function, morphine induced both interstitial fibrosis and cardiomyocyte hypertrophy. Interestingly, DRD3ag abolished these effects. Compared to naive tissues, collagen 1 increased after withdrawal in G3 and G4 and collagen 3 increased in G1-G4 but at higher levels in G1 and G2. Only G5 did not show collagen differences compared to naive, suggesting DRD3ag treatment during withdrawal may be beneficial and prevent morphine-induced fibrosis. Smad2/3 phosphorylation increased during withdrawal, indicating a likely upstream pathway for the observed morphine-induced fibrosis. Overall, our data suggest that DRD3ag adjunct therapy decreases morphine-induced adverse cardiac remodeling. (C) 2020 Elsevier Inc. All rights reserved.