title: P2Y12receptor-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 P2Y12receptor (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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesiology and Pain Medicine, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing.
authors.forename: Mingjuan
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology and Pain Medicine, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing; Department of Anesthesiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.affiliation: Department of Anesthesiology and Pain Medicine, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing.
authors.forename: Hanqi
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology and Pain Medicine, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing.
authors.forename: Longsheng
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology and Pain Medicine, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Anesthesiology and Pain Medicine, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing.
authors.forename: Bing
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology and Pain Medicine, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing.
authors.forename: Huadong
authors.initials: H
authors.lastname: Ni
authors.affiliation: Department of Anesthesiology and Pain Medicine, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing.
authors.forename: Shijie
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology and Pain Medicine, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing.
authors.forename: Xuyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Qingquan
authors.initials: Q
authors.lastname: Lian
keywords: P2Y12 receptor; cancer-induced bone pain; cytokines; p38MAPK pathway