P2X7-related modulation of pathological nociception in rats

S. McGaraughty*, K. L. Chu, M. T. Namovic, D. L. Donnelly-Roberts, R. R. Harris, X. F. Zhang, C. C. Shieh, C. T. Wismer, C. Z. Zhu, D. M. Gauvin, A. C. Fabiyi, P. Honore, R. J. Gregg, M. E. Kort, D. W. Nelson, W. A. Carroll, K. Marsh, C. R. Faltynek, M. F. Jarvis

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

Abstract

Growing evidence supports a role for the immune system in the induction and maintenance of chronic pain. ATP is a key neurotransmitter in this process. Recent studies demonstrate that the glial ATP receptor, P2X7, contributes to the modulation of pathological pain. To further delineate the endogenous mechanisms that are involved in P2X7-related antinociception, we utilized a selective P2X7 receptor antagonist, A-438079, in a series of in vivo and in vitro experiments. Injection of A-438079 (10-300 μmol/kg, i.p.) was anti-allodynic in three different rat models of neuropathic pain and it attenuated formalin-induced nocifensive behaviors. Using in vivo electrophysiology, A-438079 (80 μmol/kg, i.v.) reduced noxious and innocuous evoked activity of different classes of spinal neurons (low threshold, nociceptive specific, wide dynamic range) in neuropathic rats. The effects of A-438079 on evoked firing were diminished or absent in sham rats. Spontaneous activity of all classes of spinal neurons was also significantly reduced by A-438079 in neuropathic but not sham rats. In vitro, A-438079 (1 μM) blocked agonist-induced (2,3-O-(4-benzoylbenzoyl)-ATP, 30 μM) current in non-neuronal cells taken from the vicinity of the dorsal root ganglia. Furthermore, A-438079 dose-dependently (0.3-3 μM) decreased the quantity of the cytokine, interleukin-1β, released from peripheral macrophages. Thus, ATP, acting through the P2X7 receptor, exerts a wide-ranging influence on spinal neuronal activity following a chronic injury. Antagonism of the P2X7 receptor can in turn modulate central sensitization and produce antinociception in animal models of pathological pain. These effects are likely mediated through immuno-neural interactions that affect the release of endogenous cytokines.

Original languageEnglish (US)
Pages (from-to)1817-1828
Number of pages12
JournalNeuroscience
Volume146
Issue number4
DOIs
StatePublished - Jun 8 2007

Keywords

  • ATP
  • WDR
  • glia
  • neuropathic pain
  • purine

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'P2X<sub>7</sub>-related modulation of pathological nociception in rats'. Together they form a unique fingerprint.

Cite this