P2Y₁₂ receptor-mediated activation of spinal microglia and p38MAPK pathway contribute to cancer-induced bone pain

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 P2Y₁₂ receptor (P2Y₁₂R) and proinflammatory cytokine production play an important role in neuropathic pain generation and maintenance. However, whether P2Y₁₂R is involved in CIBP remains unknown.

The purpose of this study was to investigate the role of P2Y₁₂R 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 P2Y₁₂R through intrathecal administration of its selective antagonist MRS2395 (400 pmol/µL, 15 µL).

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).

Taken together, our present results suggest that microglial P2Y₁₂R 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.