Upregulation of Acid-Sensing Ion Channel ASIC1a in Spinal Dorsal Horn Neurons Contributes to Inflammatory Pain Hypersensitivity

J Neurosci. 2007 Oct 10;27(41):11139-48. doi: 10.1523/JNEUROSCI.3364-07.2007.

Abstract

Development of chronic pain involves alterations in peripheral nociceptors as well as elevated neuronal activity in multiple regions of the CNS. Previous pharmacological and behavioral studies suggest that peripheral acid-sensing ion channels (ASICs) contribute to pain sensation, and the expression of ASIC subunits is elevated in the rat spinal dorsal horn (SDH) in an inflammatory pain model. However, the cellular distribution and the functional consequence of increased ASIC subunit expression in the SDH remain unclear. Here, we identify the Ca2+-permeable, homomeric ASIC1a channels as the predominant ASICs in rat SDH neurons and downregulation of ASIC1a by local rat spinal infusion with specific inhibitors or antisense oligonucleotides markedly attenuated complete Freund's adjuvant (CFA)-induced thermal and mechanical hypersensitivity. Moreover, in vivo electrophysiological recording showed that the elevated ASIC1a activity is required for two forms of central sensitization: C-fiber-induced "wind-up" and CFA-induced hypersensitivity of SDH nociceptive neurons. Together, our results reveal that increased ASIC activity in SDH neurons promotes pain by central sensitization. Specific blockade of Ca2+-permeable ASIC1a channels thus may have antinociceptive effect by reducing or preventing the development of central sensitization induced by inflammation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Sensing Ion Channels
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Hyperalgesia / genetics
  • Hyperalgesia / metabolism
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation / physiopathology
  • Male
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Pain / metabolism*
  • Pain / pathology
  • Pain / physiopathology
  • Pain Measurement / methods
  • Posterior Horn Cells / metabolism*
  • Posterior Horn Cells / pathology*
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channel Blockers / pharmacology
  • Sodium Channels / biosynthesis*
  • Sodium Channels / genetics
  • Sodium Channels / physiology
  • Spider Venoms / toxicity
  • Up-Regulation / physiology*

Substances

  • Acid Sensing Ion Channels
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Sodium Channel Blockers
  • Sodium Channels
  • Spider Venoms