PT  - JOURNAL ARTICLE
AU  - Yixin Zhang
AU  - Peilan Zhou
AU  - Fengfeng Lu
AU  - Ruibin Su
AU  - Zehui Gong
TI  - ABIN-1 in the brain alleviated opioid tolerance through its action on β-arrestin2
AID  - 10.1124/molpharm.120.000211
DP  - 2021 Jan 01
TA  - Molecular Pharmacology
PG  - MOLPHARM-AR-2020-000211
4099  - http://molpharm.aspetjournals.org/content/early/2021/05/24/molpharm.120.000211.short
4100  - http://molpharm.aspetjournals.org/content/early/2021/05/24/molpharm.120.000211.full
AB  - 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. Significance Statement ABIN-1 overexpression in mice brain attenuated morphine tolerance and dependence. The mechanism may be that ABIN-1-β-arrestin-2 complex formation facilitated β-arrestin-2 degradation by ubiquitination. ABIN-1 targeted β-arrestin2 to regulate morphine tolerance Therefore, inhibiting of ABIN-1 is an important strategy to prevent morphine tolerance and dependence.