Activation of spinal chemokine receptor CXCR3 mediates bone cancer pain through an Akt-ERK crosstalk pathway in rats

Exp Neurol. 2015 Jan:263:39-49. doi: 10.1016/j.expneurol.2014.09.019. Epub 2014 Oct 2.

Abstract

Previously, we showed that activation of the spinal CXCL9, 10/CXCR3 pathway mediated bone cancer pain (BCP) in rats. However, the cellular mechanism involved is poorly understood. Here, we found that the activated CXCR3 was co-localized with either neurons, microglia, and astrocytes in the spinal cord, or non-peptidergic-, peptidergic-, and A-type neurons in the dorsal root ganglion. The inoculation of Walker-256 mammary gland carcinoma cells into the rat's tibia induced a time-dependent phosphorylation of Akt and extracellular signal-regulated kinase (ERK1/2) in the spinal cord, and CXCR3 was necessary for the phosphorylation of Akt and ERK 1/2. Meanwhile, CXCR3 was co-localized with either pAkt or pERK1/2. Blockage of either Akt or ERK1/2 prevented or reversed the mechanical allodynia in BCP rats. Furthermore, there was cross-activation between PI3K/Akt and Raf/MEK/ERK pathway under the BCP condition. Our results demonstrated that the activation of spinal chemokine receptor CXCR3 mediated BCP through Akt and ERK 1/2 kinase, and also indicated a crosstalk between PI3K/Akt and Raf/MEK/ERK signaling pathways under the BCP condition.

Keywords: Akt; Bone cancer; CXCR3; ERK; Pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Bone Neoplasms / complications
  • Bone Neoplasms / metabolism*
  • Disease Models, Animal
  • Female
  • Hyperalgesia / metabolism
  • Immunohistochemistry
  • MAP Kinase Signaling System / physiology*
  • Pain / etiology
  • Pain / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Wistar
  • Receptor Cross-Talk / physiology
  • Receptors, CXCR3 / metabolism*

Substances

  • Cxcr3 protein, rat
  • Receptors, CXCR3
  • Proto-Oncogene Proteins c-akt