Fumaric acid regulates morphine tolerance in bone cancer pain through spinal MrgC receptor modulation

Background: Bone cancer pain (BCP) represents a debilitating complication that profoundly impacts patient quality of life and predisposes to psychological comorbidities, including depression and anxiety. Objectives: To investigate the effect of fumaric acid on morphine tolerance in BCP via spinal MrgC receptors. Methods: This study adopted an in-vivo animal experiment design. The BCP mouse model was established and divided into the Vehicle group, the fumaric acid monotherapy group with different doses, the fumaric acid + morphine combination group, the normal saline + morphine control group and the fumaric acid + normal saline control group. Intervention is carried out through intrathecal administration. Pain behavior tests such as the threshold for mechanical foot retraction, the number of spontaneous foot lifts, the duration of foot lift protection and the latency period of cold pain foot retraction were evaluated. The expression level of MrgC protein in spinal cord tissue was detected by Western blotting and immunohistochemistry. Results: Fumaric acid dose-dependently attenuated BCP and delayed morphine tolerance, with EC?? values of 69.18 mg/kg (mechanical) and 99.78 mg/kg (cold). Its effects correlated with downregulation of spinal MrgC expression. Conclusion: Fumaric acid alleviates BCP and delays morphine tolerance by down-regulating the expression of spinal MrgC receptors. MrgC receptors are potential new therapeutic targets.