title: Enhancement of purinergic signalling by excessive endogenous ATP in resiniferatoxin (RTX) neuropathy.
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.
authors.affiliation: Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Chih-Lung
authors.initials: CL
authors.lastname: Lin
authors.forename: Yaw-Syan
authors.initials: YS
authors.lastname: Fu
authors.forename: Tin-Hsin
authors.initials: TH
authors.lastname: Hsiao
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Hsieh
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D004195:Disease Models, Animal; D004224:Diterpenes / Q000633:toxicity; D005455:Fluorescent Antibody Technique; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009498:Neurotoxins / Q000633:toxicity; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D004224:Diterpenes; D009498:Neurotoxins; D058477:Receptors, Purinergic P2X3; D000255:Adenosine Triphosphate; C024353:resiniferatoxin; D001081:Apyrase