Endoplasmic reticulum stress promoting caspase signaling pathway-dependent apoptosis contributes to bone cancer pain in the spinal dorsal horn

BACKGROUND: Management of bone cancer pain 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 stress is involved in many neurological and inflammatory pathways associated with pain. However, the factors that contribute to endoplasmic reticulum stress and its causes in bone cancer pain are still unknown. In this study, we examined whether the endoplasmic reticulum 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: Bone cancer pain was measured behaviorally by the paw withdrawal threshold. The expression levels of endoplasmic reticulum 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 endoplasmic reticulum kinase (p-PERK) and cleaved caspase-3, were quantitatively assessed by western blot. The distribution of p-eIF2α (an endoplasmic reticulum marker) and cleaved caspase-3 in the lumbar enlargement of the spinal cord was determined by immunohistochemistry in spinal dorsal horn slices. RESULTS: Bone cancer pain suffered bone damage and persistent mechanical allodynia. Bone cancer pain increased the expression of GRP78, ATF6, p-PERK, p-IRE1, and cleaved caspase-3 in a rat model of bone cancer pain. In addition, p-eIF2α and cleaved caspase-3 were localized to neurons. The intrathecal injection of tauroursodeoxycholic acid as a specific inhibitor of endoplasmic reticulum stress attenuated bone cancer pain 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 bone cancer pain. CONCLUSION: Endoplasmic reticulum stress causes the activation of caspase signaling pathway-dependent apoptosis in neuronal cells and induces bone cancer pain-related hyperalgesia.