Endoplasmic Reticulum Stress Promoting Caspase Signaling Pathway Dependent Apoptosis Contributes To Bone Cancer Pain

Objective: Management of bone cancer pain(BCP)is difficult because of its complex mechanisms,which has a major impact on the quality of patients' daily life.Recent studies have indicated that endoplasmic reticulum(ER)stress is involved in many neurological and inflammatory pathways associated with pain.However,the factors that contribute to ER stress and its causes in bone cancer pain are still unknown.In this study,we examined whether the ER stress response is involved in caspase signaling pathway-dependent apoptosis in neurons in the spinal dorsal horn of tumor-bearing rats and whether it thereby induces bone cancer pain.Methods: BCP was measured behaviorally by the paw withdrawal threshold(PWT).The expression levels of ER stress markers,namely,immunoglobulin-binding protein/ glucose regulated protein 78(BIP/GRP78),activating transcription factor-6(ATF6),phosphorylated inositol-requiring enzyme-1(p-IRE1),phosphorylated protein kinase RNA-like ER kinase(p-PERK)and cleaved caspase-3,were quantitatively assessed by Western blot.The distribution of p-e IF2?(an ER marker)and cleaved caspase-3 in the lumbar enlargement of the spinal cord was determined by immunohistochemistry in spinal dorsal horn slices.Tunel staining was used to detect apoptosis in the dorsal horn of the spinal cordResults: BCP suffered bone damage and persistent mechanical allodynia.BCP increased the expression of GRP78,ATF6,p-PERK,p-IRE1,and cleaved caspase-3 in a rat model of BCP.In addition,p-e IF2? and cleaved caspase-3 were localized to neurons.The intrathecal injection of tauroursodeoxycholic acid(TUD)as a specific inhibitor of ER stress attenuated BCP and reduced the expression of GRP78,ATF6,p-PERK,p-IRE1,and cleaved caspase-3 in the spinal cord.Moreover,Z-DEVD-FMK(FMK)was also shown to attenuate BCP.Conclusion: ER stress causes the activation of caspase signaling pathway-dependent apoptosis in neuronal cells and induces bone cancer pain-related hyperalgesia.