Involvement of RVM-expressed P2X7 receptor in bone cancer pain: Mechanism of descending facilitation

Abstract

Patients with bone cancer commonly experience bone pain that is severe, intolerable, and difficult to manage. The rostral ventromedial medulla (RVM) plays an important role in the development of chronic pain via descending facilitation of spinal nociception. The compelling evidence shows that glial P2X7 receptor (P2X7R) is involved in the induction and maintenance of chronic pain syndromes. The present study explored the mechanism of glial activation and P2X7R expression underlying the induction of bone cancer pain. The results demonstrated that microglia and astrocytes in the RVM were markedly activated in bone cancer rats, and the expression of P2X7R was significantly upregulated. Injection of Brilliant Blue G (BBG), an inhibitor of P2X7R, into the RVM significantly alleviated pain behaviors of cancer rats, which was supported by intra-RVM injection of RNA interference targeting the P2X7R in the RVM. It is suggested that activation of microglia-expressed P2X7R in the RVM contributes to bone cancer pain. Given that 5-HT in the RVM is involved in modulating spinal nociception, changes in 5-HT and Fos expression were addressed in the spinal cord. Inhibition of P2X7R by BBG or small-interference RNA targeting P2X7 in the RVM markedly reduced 5-HT level and Fos expression in the spinal cord. The data clearly suggest that the activation of microglial P2X7R in the RVM contributes to the development of bone cancer pain via upregulation of spinal 5HT levels by the descending pain facilitatory system.

Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods

“…While all the existing studies using this model typically assess the pain behaviors only until around 20–25 days after injection of cancer cells, our findings are the first to successfully investigate the model for up to 66 days and to show that W256 cell-induced bone pain can apparently resolve spontaneously at later stages despite the ongoing presence of cancer cells, similar to the clinical situation in humans. The beginning of resolution of pain hypersensitivity behavior around 20–25 days after surgery in this model has been observed in other studies, although these studies only assessed pain behaviors until 20–25 days (Zhao et al, 2010; Xu et al, 2013; Huang et al, 2014). A similar spontaneous reversal of mechanical hypersensitivity has been reported in rats administered a unilateral ITI of MRMT-1 cells in a BCIBP model (Falk et al, 2015).…”

Rostral ventromedial medulla‐mediated descending facilitation following P2X7 receptor activation is involved in the development of chronic post‐operative pain

“…), and cancer pain (Huang et al . ) has been suggested previously. Consistently, here we showed that descending facilitation was also involved in the development of CPSP.…”

“…) or during cancer development (Huang et al . ). The ATP‐gated P2X7 receptor (P2X7R) is predominantly present on microglia in the central nervous system.…”

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

“…Thus, the verification of tibial tumor burden post-mortem is very important. However, the beginning of pain behavior resolution at 20–25 days post-surgery is typically not due to tumor regression, but may involve neuro-immune mechanisms (Zhao et al, 2010; Xu et al, 2013; Huang et al, 2014). In previous work by others using different cancer cell lines, up regulation of the endogenous opioid system is implicated in spontaneous pain behavior resolution (Muralidharan et al, 2013).…”