A20-Binding Inhibitor of Nuclear Factor-κB Targets β-Arrestin2 to Attenuate Opioid Tolerance

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 ABIN-1 in modulating morphine function. We used hotplate tests and CPP tests to show that overexpression of ABIN-1 in the mice 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 MOR phosphorylation and internalization following 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.

Insight into the regulatory mechanism of β‐arrestin2 and its emerging role in diseases

“…β ‐Arrestin2 mediates the internalization of μ opioid receptors and promotes morphine tolerance (Kliewer et al, 2019). A recent study demonstrated that A20‐binding inhibitor of nuclear factor‐κB (ABIN‐1) interacted with β ‐arrestin2, which accelerated β ‐arrestin2 degradation via ubiquitination and attenuated morphine tolerance (Zhang et al, 2021). Acute alcohol exposure elicits various behavioural and neurobiological responses, including feelings of euphoria, loss of coordination and cognitive impairment.…”