A20-Binding Inhibitor of Nuclear Factor-κB Targetsβ-Arrestin2 to Attenuate Opioid Tolerance,Molecular Pharmacology

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A20-Binding Inhibitor of Nuclear Factor-κB Targetsβ-Arrestin2 to Attenuate Opioid Tolerance
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2021-08-01 , DOI: 10.1124/molpharm.120.000211
Yixin Zhang ₁ , Peilan Zhou ₂ , Fengfeng Lu ₁ , Ruibin Su ₂ , Zehui Gong ₁

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Opioids play an important role in pain relief, but repeated exposure results in tolerance and dependence. To make opioids more effective and useful, research in the field has focused on reducing the tolerance and dependence for chronic pain relief. Here, we showed the effect of A20-binding inhibitor of nuclear factor-κB (ABIN-1) in modulating morphine function. We used hot-plate tests and conditioned place preference (CPP) tests to show that overexpression of ABIN-1 in the mouse brain attenuated morphine dependence. These effects of ABIN-1 are most likely mediated through the formation of ABIN-1–β-arrestin2 complexes, which accelerate β-arrestin2 degradation by ubiquitination. With the degradation of β-arrestin2, ABIN-1 overexpression also decreased μ opioid receptor (MOR) phosphorylation and internalization after opioid treatment, affecting the β-arrestin2–dependent signaling pathway to regulate morphine tolerance. Importantly, the effect of ABIN-1 on morphine tolerance was abolished in β-arrestin2–knockout mice. Taken together, these results suggest that the interaction between ABIN-1 and β-arrestin2 inhibits MOR internalization to attenuate morphine tolerance, revealing a novel mechanism for MOR regulation. Hence, ABIN-1 may be a therapeutic target to regulate MOR internalization, thus providing a foundation for a novel treatment strategy for alleviating morphine tolerance and dependence.

中文翻译：

核因子-κB 的 A20 结合抑制剂靶向 β-Arrestin2 以减弱阿片类药物耐受

阿片类药物在缓解疼痛方面发挥着重要作用，但反复接触会导致耐受和依赖。为了使阿片类药物更有效和有用，该领域的研究集中在降低慢性疼痛缓解的耐受性和依赖性上。这里，我们发现核因子的A20结合抑制剂的效果κ在调节吗啡函数B（ABIN-1）。我们使用热板测试和条件位置偏好 (CPP) 测试来表明小鼠大脑中 ABIN-1 的过度表达减弱了吗啡依赖。ABIN-1 的这些作用很可能是通过形成 ABIN-1- β - arrestin2 复合物介导的，该复合物通过泛素化加速β- arrestin2 降解。随着β的降解-arrestin2、ABIN-1 过表达还降低了阿片类药物治疗后μ阿片受体 (MOR) 的磷酸化和内化，影响了β -arrestin2 依赖性信号通路以调节吗啡耐受。重要的是，ABIN-1 对吗啡耐受性的影响在β -arrestin2 基因敲除小鼠中被消除。总之，这些结果表明 ABIN-1 和β - arrestin2之间的相互作用抑制 MOR 内化以减弱吗啡耐受，揭示了 MOR 调节的新机制。因此，ABIN-1 可能是调节 MOR 内化的治疗靶点，从而为减轻吗啡耐受和依赖的新治疗策略提供基础。

更新日期：2021-08-31

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