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

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Abstract

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.

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Acknowledgements

This work was supported by grants from the National Science Council (NSC100-2320-B-037-018) and Kaohsiung Medical University Research Foundation (KMU-Q098015, KMU-Q099005, and KMU-M100004).

Conflicts of interests

The authors declare that they have no conflicts of interests.

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Authors and Affiliations

  1. Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan

    Chih-Lung Lin

  2. Faculty of Medicine, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan

    Chih-Lung Lin

  3. Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan

    Yaw-Syan Fu

  4. Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, 80708, Taiwan

    Tin-Hsin Hsiao & Yu-Lin Hsieh

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  1. Chih-Lung Lin
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  2. Yaw-Syan Fu
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Correspondence to Yu-Lin Hsieh.

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Lin, CL., Fu, YS., Hsiao, TH. et al. Enhancement of purinergic signalling by excessive endogenous ATP in resiniferatoxin (RTX) neuropathy. Purinergic Signalling 9, 249–257 (2013). https://doi.org/10.1007/s11302-012-9347-y

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