Intrathecal morphine pretreatment ameliorated hepatic ischemia-reperfusion injury by reducing inflammation through peripheral and spinal opioid activation in rats

Background Hepatic ischemia-reperfusion injury (IRI) is a common phenomenon after liver transplantation and liver tumor surgery. Morphine provides analgesia and prevents hepatic IRI. Besides morphine in the spinal cord has the protective effect on hepatic IRI. But the mechanism has not been well characterized. This study investigated whether morphine administrated intrathecally mimic the protective effect by reducing inflammation, and whether this kind of effect was mediated by phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Methods We established models of hepatic IRI and intrathel catheter insertion on Sprague-Dawley. Morphine was administrated 10min prior hepatic ischemia flowed with 6h reperfusion. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histological changes and liver cell apoptosis assessed liver IRI. Similar maneuvers were repeated using the optimal dose and opioid receptor antagonist naloxone methiodide (NM). Serum ALT and AST, histological staining, hepatic apoptosis and serum levels of tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) were assessed. Expression of Akt and its downstream protein Erk were evaluated by Western blotting. Results Morphine pretreatment intrathecally at dose of 10μg·mg -1 reduced ALT and AST levels, hepatic apoptosis, inflammation and preserved liver structure. These changes were partially reserved by NM 10min prior morphine injection. Morphine elevated the expression of Akt and Erk, however, NM did not decrease Akt and Erk expression. Conclusion Intrathecal morphine pretreatment reduced rats’ livers’ inflammation through both peripheral and spinal opioid receptors activation. The potential mechanism contributed to moderate PI3K/Akt pathway.

Spinal opioid analgesia in the rat

It is hard to imagine a time when the world of science and medicine did not know that morphine or other opioids administered to the spinal cord produced analgesia. However, this was the current state of knowledge in the early 1970s before the studies of Yaksh and Rudy created one of the most important paradigm shifts in the treatment of pain. The landmark paper is a pharmacology paper describing the results of the first comprehensive study of spinal opioid analgesia in the rat. The study produced the first full dose-response curves for morphine, fentanyl, methadone, and meperidine and proved a spinal site of opioid action. Classic pharmacological analysis yielded a competitive interaction at a single site, the as-yet undiscovered opioid receptors. Most importantly, with this paper, Yaksh and colleagues began a lifetime of cutting-edge research that would reveals the complex nature of pain processing and numerous classes of analgesic agents.