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

Abstract

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 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.

Methods

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).

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 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.

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Keywords:

• P2Y₁₂ receptor
• cancer-induced bone pain
• p38MAPK pathway
• cytokines

Acknowledgments

This study was supported by funding from the Natural Science Foundation of Zhejiang Province (LY16H090016 and LY17H090019), the Zhejiang Provincial and Ministerial Cultivation Plan for Medicine and Health (2015PY010), the National Natural Science Foundation of China (81341035 and 81171057), the Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents (2012-RC-22), Zhejiang Province, Zhejiang north regional, the construction projects of Anesthesia Discipline Special Disease Center, and Jiaxing City, the construction projects of Key Laboratory of Nerve and Pain Medicine, and construction funding of Medicine Key Discipline of Pain Therapy, Integrated Traditional and Western Medicine of Zhejiang Province (2012-XK-A31). The authors acknowledge the technical support from the Central Laboratory of the First Hospital of Jiaxing. We also thank Professor Renshan Ge, a native speaker, the former head of the Endocrinology Lab of the CBR in Population Council (USA) for English language editing.

Author contributions

All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.