Remifentanil preconditioning promotes liver regeneration via upregulation of ß-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 µg/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 ß-arrestin 2 in vivo and in vitro. Demonstrating specificity, remifentanil preconditioning failed to promote liver regeneration in liver-specific ß-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 significantly 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 ß-arrestin 2/ERK/cyclin D1 axis, with implications for improving regeneration process after hepatectomy.

G protein-coupled estrogen receptor in the rostral ventromedial medulla contributes to the chronification of postoperative pain.

AIMS: Chronification of postoperative pain is a common clinical phenomenon following surgical operation, and it perplexes a great number of patients. Estrogen and its membrane receptor (G protein-coupled estrogen receptor, GPER) play a crucial role in pain regulation. Here, we explored the role of GPER in the rostral ventromedial medulla (RVM) during chronic postoperative pain and search for the possible mechanism. METHODS AND RESULTS: Postoperative pain was induced in mice or rats via a plantar incision surgery. Behavioral tests were conducted to detect both thermal and mechanical pain, showing a small part (16.2%) of mice developed into pain persisting state with consistent low pain threshold on 14 days after incision surgery compared with the pain recovery mice. Immunofluorescent staining assay revealed that the GPER-positive neurons in the RVM were significantly activated in pain persisting rats. In addition, RT-PCR and immunoblot analyses showed that the levels of GPER and phosphorylated µ-type opioid receptor (p-MOR) in the RVM of pain persisting mice were apparently increased on 14 days after incision surgery. Furthermore, chemogenetic activation of GPER-positive neurons in the RVM of Gper-Cre mice could reverse the pain threshold of pain recovery mice. Conversely, chemogenetic inhibition of GPER-positive neurons in the RVM could prevent mice from being in the pain persistent state. CONCLUSION: Our findings demonstrated that the GPER in the RVM was responsible for the chronification of postoperative pain and the downstream pathway might be involved in MOR phosphorylation.