ABIN-1 in the brain alleviates opioid tolerance by interacting with
β-arrestin2 and MOR
Background: While opioids play a crucial role in pain’s relief, chronic
exposure results in tolerance and dependence. Efforts should be made to
alleviate the side effect induced by opioids. Many proteins which
functionally interact with MOR can regulate the effect of opioids. Our
bacterial yeast two-hybrid experiment showed ABIN-1 could bind to MOR.
Here, we studied the profile and mechanism of ABIN-1 on morphine
tolerance and dependence. Experimental Approach: ABIN-1 in mouse brain
was interfered by AAV virus. The tolerance and dependence induced by
morphine were assessed in hotplate and conditioned place preference
test. The regulation of β-arrestin signalling of MOR was observed in
MOR-CHO cell lines after ABIN-1 overexpression. The interaction of
proteins was detected by co-immunoprecipitation and immunofluorescence.
The expression of proteins was tested by western blotting and
immunohistochemistry. Key Results: Morphine tolerance and dependence
were attenuated by overexpression of ABIN-1 in mouse brains. ABIN-1 in
the hippocampus and nucleus accumbens participated in morphine tolerance
and physical dependence. MOR phosphorylation and internalization were
weakened by ABIN-1 after opioids treatment. Formation of
ABIN-1-β-arrestin-2 complexes promoted the translocation of β-arrestin-2
to the plasma membrane and accelerated its ubiquitination and
degradation. Furthermore, attenuation of morphine tolerance by ABIN-1
was abolished in β-arrestin-2 knockout mice. Conclusions and
Implications: These findings indicate that ABIN-1 co-operates with
β-arrestin2 and MOR to alleviate morphine tolerance and dependence.
ABIN-1 may be a target to alleviate morphine tolerance.