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The CUL3/neddylation inhibitor MLN4924 reduces ethanol-induced locomotor sensitization and inflammatory pain allodynia in mice
Behavioural Brain Research ( IF 2.7 ) Pub Date : 2020-12-03 , DOI: 10.1016/j.bbr.2020.113051
Zhong Ding 1 , Gregory T Knipp 2 , Richard M van Rijn 3 , Julia A Chester 4 , Val J Watts 3
Affiliation  

Heterologous sensitization of adenylyl cyclase (AC) is defined by an enhanced cAMP response following persistent activation of Gαi/o-coupled receptors. This phenomenon was first observed in cellular models, and later reported in animal models of inflammatory pain or following chronic exposure to drugs of abuse including opioids and cocaine. Recently, we used genome-wide siRNA screening to identify Cullin3 signaling as a mediator of AC sensitization in cellular models. We also showed that pharmacological inhibition of Cullin3 with the neddylation inhibitor, MLN4924, abolished heterologous sensitization of several AC isoforms, including AC1, AC2, AC5, and AC6. Because ACs, especially AC1, have been implicated in alcohol-induced locomotor sensitization and inflammatory pain, we assessed the potential activity of MLN4924 in both murine models. We found that MLN4924 (30 mg/kg, i.p.) accumulated in the brain and reduced both locomotor sensitization induced by repeated alcohol administration and allodynia in an inflammatory pain model. Based on our previous findings that MLN4924 potently blocks AC sensitization in cellular models, we propose that the activity of MLN4924 in both animal models potentially occurs through blocking AC sensitization. Our findings provide the basis for understanding the molecular mechanism and yield a new pathway for drug development for pathological disorders associated with AC sensitization.



中文翻译:

CUL3/neddylation 抑制剂 MLN4924 可降低乙醇诱导的小鼠运动致敏性和炎症性疼痛异常性疼痛

腺苷酸环化酶 (AC) 的异源致敏由 Gα i/o持续激活后 cAMP 反应增强来定义-偶联受体。这种现象首先在细胞模型中观察到,后来在炎症性疼痛的动物模型中或在长期暴露于包括阿片类药物和可卡因在内的滥用药物后报告。最近,我们使用全基因组 siRNA 筛选来鉴定 Cullin3 信号传导作为细胞模型中 AC 致敏的介质。我们还表明,用 neddylation 抑制剂 MLN4924 对 Cullin3 的药理学抑制消除了几种 AC 同种型的异源致敏,包括 AC1、AC2、AC5 和 AC6。因为 ACs,尤其是 AC1,与酒精诱导的运动致敏和炎症性疼痛有关,我们评估了 MLN4924 在两种小鼠模型中的潜在活性。我们发现 MLN4924 (30 mg/kg, ip.) 积聚在大脑中,并降低炎症性疼痛模型中反复饮酒和异常性疼痛引起的运动敏感性。基于我们先前的发现,即 MLN4924 在细胞模型中有效阻断 AC 致敏,我们提出 MLN4924 在两种动物模型中的活性可能通过阻断 AC 致敏发生。我们的研究结果为理解分子机制提供了基础,并为与 AC 致敏相关的病理疾病的药物开发提供了新途径。

更新日期:2020-12-08
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