P2Y Receptor-mediated Activation of Spinal Microglia and P38MAPK Pathway Contribute to Cancer-induced Bone Pain

Background: Cancer-induced bone pain (CIBP) is one of the most challenging clinical problems due to a lack of understanding the mechanisms. Recent evidence has demonstrated that activation of microglial G-protein-coupled P2Y receptor (P2YR) and proinflammatory cytokine production play an important role in neuropathic pain generation and maintenance. However, whether P2YR is involved in CIBP remains unknown.

Methods: The purpose of this study was to investigate the role of P2YR in CIBP and its molecular mechanisms. Using the bone cancer model inoculated with Walker 256 tumor cells into the left tibia of Sprague Dawley rat, we blocked spinal P2YR through intrathecal administration of its selective antagonist MRS2395 (400 pmol/µL, 15 µL).

Results: We found that not only the ionized calcium-binding adapter molecule 1 (Iba-1)-positive microglia in the ipsilateral spinal cord but also mechanical allodynia was significantly inhibited. Furthermore, it decreased the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and the production of proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6), whereas it increased tumor necrosis factor-α (TNF-α).

Conclusion: Taken together, our present results suggest that microglial P2YR in the spinal cord may contribute to CIBP by the activation of spinal microglia and p38MAPK pathway, thus identifying a potential therapeutic target for the treatment of CIBP.