A20-binding inhibitor of nuclear factor-κb targets β-arrestin2 to attenuate opioid tolerance

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Abstract

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 factorκB (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 l 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.

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Zhang, Y., Zhou, P., Lu, F., Su, R., & Gong, Z. (2021). A20-binding inhibitor of nuclear factor-κb targets β-arrestin2 to attenuate opioid tolerance. Molecular Pharmacology, 100(2), 170–180. https://doi.org/10.1124/MOLPHARM.120.000211

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