Hepatic ischemia reperfusion injury occurs in a series of surgery related settings,which restrict the development of liver surgery for a long period.Recent studies have demonstrated that down regulation of inflammatory pathway by opioid agonist remifentanil conferred ideal hepatic protection.However,remifentanil anti-inflammatory mechanism remains unclear.In this study,we report that remifentanil alleviate HIRI in mice through inhibiting TLR4 pathway.Interestingly,remifentanil increases β-arrestin2 expression both in vivo and vitro experiments.To further investigate the detail mechanism of β-arrestin2 play in opioid anti-inflammatory process,we use siRNA targeting β-arrestin2 in RAW264.7 macrophage cells,and the results show that deficiency of β-arrestin2 block remifentanil protective effect of relieving the cell death and apoptosis through MAPK activity.The present research firstly demonstrates thatβ-arrestin2 is the key molecule in bridging opioid receptor and TLR4 pathway,which further clarify opioid anti-inflammatory mechanism,and provide theoretical evidence and experimental basis for the clinical practicability of opioid agonist in liver protection.