Over-expression of astrocytic ET-1 attenuates neuropathic pain by inhibition of ERK1/2 and Akt(s) via activation of ETA receptor

Mol Cell Neurosci. 2014 May;60:26-35. doi: 10.1016/j.mcn.2014.02.007. Epub 2014 Mar 1.

Abstract

A differential role of endothelin-1 (ET-1) in pain processing has recently been suggested. However, the function of central ET-1 in neuropathic pain (NP) has not been fully elucidated to date. We report here the action of endogenous central ET-1 in sciatic nerve ligation-induced NP (SNL-NP) in a transgenic animal model that over-expresses ET-1 in the astrocytes (GET-1 mice). We hypothesized that the over-expression of astrocytic ET-1 would exert anti-allodynic and anti-hyperalgesic effects in NP, as demonstrated by mechanical threshold and plantar withdrawal latency using the von Frey filament and heat stimuli. In our animal model, GET-1 mice showed an increase in the withdrawal threshold and latency in response to the mechanical and thermal stimuli, respectively, in pain behavior tests after SNL. ET-1 and endothelin type A receptor (ETA-R) levels were increased significantly in L4-L6 segments of the spinal cord (ipsilateral to SNL) of GET-1 mice at 7 and 21days after surgery. Moreover, intrathecal administration of a specific ETA-R antagonist, BQ-123, attenuated the anti-allodynic and anti-hyperalgesic phenotype in GET-1 mice. The effects of BQ-123 on the mRNA expression of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and protein kinase B/serine protein kinase (Akt(s)) were assessed in the ipsilateral L4-L6 segments harvested 30min after BQ-123 administration on day 7 after surgery. Phosphorylation of ERK1/2 and Akt(s) in the ipsilateral spinal cord of GET-1 mice was reduced following SNL, whereas no reduction was observed after intrathecal injection of BQ-123. In conclusion, our results showed that the xover-expression of astrocytic ET-1 reduced SNL-induced allodynia and hyperalgesia by inhibiting the activation of ERK1/2 and Akt(s) via the ETA-R-mediated pathway.

Keywords: Allodynia; Astrocytes; Endothelin-1; Hyperalgesia; Neuropathic pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Endothelin Receptor Antagonists / pharmacology
  • Endothelin Receptor Antagonists / therapeutic use*
  • Endothelin-1 / genetics
  • Endothelin-1 / metabolism*
  • Hot Temperature
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neuralgia / drug therapy
  • Neuralgia / metabolism*
  • Peptides, Cyclic / pharmacology
  • Peptides, Cyclic / therapeutic use*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reaction Time
  • Receptor, Endothelin A / metabolism*
  • Sciatic Nerve / injuries
  • Sciatic Nerve / metabolism
  • Touch

Substances

  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Peptides, Cyclic
  • Receptor, Endothelin A
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • cyclo(Trp-Asp-Pro-Val-Leu)