-Elemene Improves Morphine Tolerance in Bone Cancer Pain via N-Methyl-D-Aspartate Receptor 2B Subunit-Mediated -Opioid Receptor.

Background: Improving morphine tolerance (MT) is an urgent problem in the clinical treatment of bone cancer pain. Considering that -Elemene is widely used in the treatment of cancer pain, we explored the effects and mechanism of -Elemene in preventing MT of bone cancer pain.

Method: Bone cancer pain and chronic MT rat model was established by injecting MADB106 cells and morphine (10 mg/kg). SH-SY5Y cells were treated with morphine (10 g/mL) for 48 h to establish a cell model. The mechanical withdrawal threshold and thermal withdrawal latency of rats were detected by mechanical allodynia and thermal hyperalgesia tests, respectively. The protein expressions of -opioid receptor (MOPR), cyclic adenosine monophosphate (cAMP), N-methyl-D-aspartate receptor subunit 2B (NR2B), phosphorylated-calmodulin-dependent protein kinase II (p-CaMKII), and CaMKII were detected by western blot. The viability of SH-SY5Y cells was determined by the cell counting kit-8 assay. cAMP content in SH-SY5Y cells was measured by a LANCE cAMP kit.

Result: Animal experiments showed that MT strengthened over time, while increased -Elemene dosage alleviated MT. The viability of SH-SY5Y cells was down-regulated by high-dose -Elemene. In the rat and cell models, long-term morphine treatment decreased the expression of MOPR and increased the cAMP and NR2B expressions and p-CaMKII/CaMKII, while -Elemene and siNR2B counteracted the effects of morphine treatment. In addition, siNR2B reversed the effects of -Elemene on related protein expressions and cAMP content in the cell model.

Conclusion: -Elemene improved MT in bone cancer pain through the regulation of NR2B-mediated MOPR.