Remifentanil preconditioning promotes liver regeneration via upregulation of β-arrestin 2/ERK/cyclin D1 pathway

Remifentanil is a potent, short-acting opioid analgesic drug that can protect tissues from ischemia and reperfusion injury though anti-inflammatory effects. However, the utility of remifentanil in liver regeneration after hepatectomy is not known. Using a 70% hepatectomy mouse model (PHx), we found that preconditioning animals with 4 mu g/kg remifentanil enhanced liver regeneration through supporting hepatocyte proliferation but not through anti-inflammatory effects. These effects were also phenocopied in vitro where 40 mM remifentanil promoted the proliferation of primary mouse hepatocyte cultures. We further identified that remifentanil treatment increased the expression of beta-promote liver regeneration in liver-specific beta-arrestin 2 knockout (CKO) mice subjected to PHx. While remifentanil increased the expression of activated (phosphorylated)-ERK and cyclin D1 in PHx livers, their levels were not signifi-cantly changed in remifentanil-treated CKO mice nor in WT mice pretreated with the ERK inhibitor U0126. Our findings suggest that remifentanil promotes liver regeneration via upregulation of a beta-arrestin 2/ERK/cyclin D1 axis, with implications for improving regeneration process after hepatectomy. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

Remifentanil enhances liver regeneration by promoting hepatocyte proliferation rather than anti-inflammatory effects. This effect was confirmed both in vitro and in vivo, and the underlying mechanism may involve the beta-arrestin 2/ERK/cyclin D1 axis.