Study On The Mechanism Of Morphine Tolerance About Tanshinone ? A Regulation JNK/c-Jun Signal Pathways

Background:Morphine is a commonly used analgesic for patients with cancer pain.However,with repeated use of morphine,the analgesic effect will decrease,which is called morphine tolerance.In addition to the reduced analgesic effect,adverse reactions such as constipation,nausea and vomiting,dizziness,drowsiness,dyspnea,and dysuria may occur,which seriously affect the quality of life of patients with cancer pain and restrict the clinical application of morphine.However,at present,the reasons for morphine tolerance and how to reduce morphine tolerance are still unclear.Therefore,the research to clarify the reasons for morphine tolerance and how to reduce morphine tolerance has important practical and theoretical significance.In recent years,a large number of studies have shown that MAPK signaling pathway and glial cells play an important role in the development of morphine analgesia tolerance.The JINK-c-Jun pathway mediated by spinal astrocytes has been confirmed to play an important role in the formation of morphine analgesic tolerance.Tanshinone IIA is the highest content and most stable active ingredient in tanshinone.It has clear antioxidant and anti-inflammatory effects and has broad prospects in the treatment of cardiovascular and cerebrovascular diseases,tumors and other diseases.Studies have reported that Tanshinone IIA can reduce the levels of IL-1?,IL-6 and TNF-? cytokines to exert anti-inflammatory effects.In addition,it can also reduce the expression of p-JNK in the spinal dorsal horn to produce analgesic effects.Therefore,we proposed whether Tanshinone IIA can inhibit the activation of the JNK-c-Jun pathway caused by morphine tolerance and reduce the inflammation to relieve morphine tolerance to further development and utilization of Tanshinone IIA and alleviate morphine Tolerate clinical application and provide experimental basis.Goal:In vivo and in vitro experiments were conducted to explore the effect and mechanism of Tanshinone ?A in relieving morphine tolerance.Method:In vivo experiment:the rat model of morphine tolerance was used,the hot-water tail flick test was used to evaluate the effect of Tanshinone II A on alleviating morphine analgesic tolerance,and the ELISA method was used to detect IL-1?,IL-6 and TNF-? in the rat spinal cord to explore the effect of Tanshinone II A from the perspective of inhibiting inflammation,Western blotting was used to determine the expression of GFAP,p-JNK,and p-c-Jun in each group of rats to explore possible mechanisms of action.In vitro experiment:primary culture rat astrocytes was cultured,ELISA method to detect the levels of IL-1?,IL-6 and TNF-a inflammatory factors in the cell supernatant,Western blotting method to determine cell GFAP,p-JNK,The expression of p-c-Jun protein to explore the mechanism of Tanshinone ?A alleviating morphine tolerance.Results:1.It can significantly reduce the levels of IL-1?,IL-6 and TNF-? in the spinal cord of morphine tolerance model rats,and reduce the expression of p-JNK,p-c-Jun in the spinal cord of morphine tolerance model rats.2.In vitro experiments found that Tanshinone IIA can inhibit the activation of astrocytes caused by morphine tolerance,and inhibit the phosphorylation of JNK,c-Jun and the protein levels of IL-1?,IL-6 and TNF-? caused by morphine tolerance.Conclusion:Tanshinone IIA can significantly decrease the analgesic tolerance of morphine both in vivo and in vitro.Its mechanism of action is related to inhibiting the phosphorylation of JNK and c-Jun and reducing the inflammation caused by the activation of glial cells.The results provide experimental basis for the Further develop and clinical utilize of morphine.