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

BACKGROUND: Improving morphine tolerance (MT) is an urgent problem in the clinical treatment of bone cancer pain. Considering that β-Elemene is widely used in the treatment of cancer pain, we explored the effects and mechanism of β-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 μg/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 μ-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 β-Elemene dosage alleviated MT. The viability of SH-SY5Y cells was down-regulated by high-dose β-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 β-Elemene and siNR2B counteracted the effects of morphine treatment. In addition, siNR2B reversed the effects of β-Elemene on related protein expressions and cAMP content in the cell model. CONCLUSION: β-Elemene improved MT in bone cancer pain through the regulation of NR2B-mediated MOPR.