Resveratrol attenuates bone cancer pain through regulating the expression levels of ASIC3 and activating cell autophagy

Bone cancer pain （BCP） is one of the most common pains in patients with malignant cancers. The mechanism underlying BCP is largely unknown. Our previous studies and the increasing evidence both have shown that acid-sensing ion channels 3 （ASIC3） is an important protein in the pathological pain state in some pain models. We hypothesized that the expression change of ASlC3 might be one of the factors related to BCP. In this study, we established the BCP model through intrathecally injecting rat mammary gland carcinoma cells （MRMT-1） into the left tibia of Sprague-Dawley female rats, and found that the BCP rats showed bone destruction, increased mechanical pain sensitivities and up-regulated ASIC3 protein expression levels in L4-L6 dorsal root ganglion. Then, resveratrol, which was intraperitoneally injected into the BCP rats on post-operative Day 21, dose-dependently increased the paw withdrawal threshold of BCP rats, reversed the pain behavior, and had an antinociceptive effect on BCP rats. In ASIC3-transfected SH-SY5Y cells, the ASIC3 protein expression levels were regulated by resveratrol in a dose- and time-dependent manner. Meanwhile, resveratrol also had an antinociceptive effect in ASIC3-mediated pain rat model. Furthermore, resveratrol also enhanced the phosphorylation of AMPK, SIRT1, and LC3-Ⅱ levels in ASIC3-transfected SH-SY5Y cells, indicating that resveratrol could activate the AMPK-SIRTl-autophagy signal pathway in ASIC3-transfected SH-SY5Y cells. In BCP rats, StRT1 and LC3-11 were also down-regulated, These findings provide new evidence for the use of resveratrol as a therapeutic treatment during BCP states.