Roles of tumor necrosis factor-α and interleukin-6 in regulating bone cancer pain via TRPA1 signal pathway and beneficial effects of inhibition of neuro-inflammation and TRPA1

摘要

Background: Pain is one of the most common and distressing symptoms suffered by patients with progression of bonecancer; however, the mechanisms responsible for hyperalgesia are not well understood. The purpose of our current studywas to determine contributions of the sensory signaling pathways of inflammatory tumor necrosis factor-a and interleukin-6and downstream transient receptor potential ankyrin 1 (TRPA1) to neuropathic pain induced by bone cancer. We furtherdetermined whether influencing these pathways can improve bone cancer pain.Methods: Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats to induce mechanicaland thermal hyperalgesia. ELISA and western blot analysis were used to examine (1) the levels of tumor necrosis factor-a andinterleukin-6 in dorsal root ganglion and (2) protein expression of tumor necrosis factor-a and interleukin-6 receptors(TNFR1 and IL-6R) and TRPA1 as well as intracellular signals (p38-MAPK and JNK).Results: Tumor necrosis factor-a and interleukin-6 were elevated in the dorsal root ganglion of bone cancer rats, andexpression of TNFR1, IL-6R, and TRPA1 was upregulated. In addition, inhibition of TNFR1 and IL-6R alleviated mechanicaland thermal hyperalgesia in bone cancer rats, accompanied with downregulated TRPA1 and p38-MAPK and JNK.Conclusions: We revealed specific signaling pathways leading to neuropathic pain during the development of bone cancer,including tumor necrosis factor-a-TRPA1 and interleukin-6-TRPA1 signal pathways. Overall, our data suggest that blockingthese signals is beneficial to alleviate bone cancer pain.