Enhancement of purinergic signalling by excessive endogenous ATP in resiniferatoxin (RTX) neuropathy

Purinergic Signal. 2013 Jun;9(2):249-57. doi: 10.1007/s11302-012-9347-y. Epub 2012 Dec 20.


ATP is a ligand of P2X family purinoceptors, and exogenous ATP administration evokes pain behaviors. To date, there is a lack of systematic studies to address relationships between endogenous ATP and neuropathic pain. In this report, we took advantage of a mouse model of resiniferatoxin (RTX)-induced neuropathic pain to address the role of endogenous ATP in neuropathic pain. After RTX administration, endogenous ATP markedly increased in dorsal root ganglia (DRGs) (p < 0.01) and skin tissues (p < 0.001). The excessive endogenous ATP was removed by apyrase, an ATP hydrolyzing enzyme, administration via either a lumbar puncture route (p < 0.001) or an intraplantar injection (p < 0.001), which led to the normalization of neuropathic pain. In addition, intraplantar treatment with apyrase caused mechanical analgesia. Linear analyses showed that the densities of P2X3(+) neurons (r = -0.72, p < 0.0001) and P2X3(+) dermal nerves (r = -0.72, p < 0.0001) were inversely correlated with mechanical thresholds. Moreover, the contents of endogenous ATP in skin tissues were linearly correlated with P2X3(+) dermal nerves (r = 0.80, p < 0.0001) and mechanical thresholds (r = -0.80, p < 0.0001). In summary, this study demonstrated that enhanced purinergic signalling due to an increase in endogenous ATP after RTX-induced nerve injury contributed to the development of neuropathic pain. The data in this report provide a new therapeutic strategy for pain control by targeting the endogenous ligand of purinergic signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis*
  • Animals
  • Apyrase / pharmacology
  • Disease Models, Animal
  • Diterpenes / toxicity
  • Fluorescent Antibody Technique
  • Male
  • Mice
  • Mice, Inbred ICR
  • Neuralgia / chemically induced
  • Neuralgia / metabolism*
  • Neuralgia / physiopathology
  • Neurotoxins / toxicity
  • Receptors, Purinergic P2X3 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*


  • Diterpenes
  • Neurotoxins
  • Receptors, Purinergic P2X3
  • Adenosine Triphosphate
  • resiniferatoxin
  • Apyrase