Remifentanil, an ultra-short acting opiate, has been reported to protect against hepatic ischemia-reperfusion injury, which is a major cause of postoperative liver dysfunction. The objective of this study was to determine whether a central vagal pathway is involved in this protective procedure. Rat models of hepatic ischemia-reperfusion were used in the experimental procedures. The results revealed that intravenous pretreatment with remifentanil decreased serum aminotransferases and hepatic histologic damage; however, an intraperitoneal injection of μ-opioid receptor antagonist did not abolish the protection of remifentanil preconditioning. c-Fos immunofluorescence of the brain stem showed that dorsal motor nucleus of the vagus was activated after remifentanil preconditioning. Moreover, serum alanine aminotransferase, histopathologic damage, and apoptosis decreased in remifentanil preconditioning group compared to vagotomized animals with remifentanil preconditioning, and there was no statistical difference of TNF-α and IL-6 between NS/Va and RPC/Va groups. In addition, remifentanil microinjection into dorsal vagal complex decreased serum aminotransferases, inflammatory cytokines, and hepatic histologic injury and apoptosis, and these effects were also abolished by a peripheral hepatic vagotomy. In conclusion, remifentanil preconditioning conferred liver protection against ischemia-reperfusion injury, which was mediated by the central vagal pathway.
Our previous study demonstrated that remifentanil, an opioid agonist, conferred profound liver protection during hepatic ischemia reperfusion injury (HIRI), in which Toll-like receptors (TLRs) played a crucial role in mediating the inflammatory responses. β-arrestin2, a well-known mu opioid receptor desensitizer, is also a negatively regulator of Toll-like receptor 4 (TLR4)-mediated inflammatory reactions in a mitogen-activated protein kinase (MAPK)-dependent manner. Using the rodent models of hepatic ischemia reperfusion injury both in wild type and TLR4 knockout (TLR4 KO) mice, we found that remifentanil preconditioning could inhibit the expression of TLR4 and reduce the inflammatory response induced by HIRI in wild type but not in TLR4 KO mice. For the in-vitro study, LPS was used to treat RAW264.7 macrophage cells to mimic the inflammatory response induced by HIRI. Remifentanil increased β-arrestin2 expression both in vivo and in vitro, while after silencing β-arrestin2 RNA, the effect of remifentanil in reducing cell death and apoptosis, as well as decreasing phosphorylation of ERK and JNK were abolished in RAW264.7 cells. These data suggested that remifentanil could ameliorate mice HIRI through upregulating β-arrestin2 expression, which may function as a key molecule in bridging opioid receptor and TLR4 pathway.
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