Excess intracellular ATP causes neuropathic pain following spinal cord injury

Nobuhiko Nakajima, Yuichiro Ohnishi, Masamichi Yamamoto, Daiki Setoyama, Hirohiko Imai, Tomofumi Takenaka, Mari Matsumoto, Koichi Hosomi, Yoichi Saitoh, Hidemasa Furue, Haruhiko Kishima

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Intractable neuropathic pain following spinal cord injury (NP-SCI) reduces a patient’s quality of life. Excessive release of ATP into the extracellular space evokes neuroinflammation via purinergic receptor. Neuroinflammation plays an important role in the initiation and maintenance of NP. However, little is known about whether or not extracellular ATP cause NP-SCI. We found in the present study that excess of intracellular ATP at the lesion site evokes at-level NP-SCI. No significant differences in the body weight, locomotor function, or motor behaviors were found in groups that were negative and positive for at-level allodynia. The intracellular ATP level at the lesion site was significantly higher in the allodynia-positive mice than in the allodynia-negative mice. A metabolome analysis revealed that there were no significant differences in the ATP production or degradation between allodynia-negative and allodynia-positive mice. Dorsal horn neurons in allodynia mice were found to be inactivated in the resting state, suggesting that decreased ATP consumption due to neural inactivity leads to a build-up of intracellular ATP. In contrast to the findings in the resting state, mechanical stimulation increased the neural activity of dorsal horn and extracellular ATP release at lesion site. The forced production of intracellular ATP at the lesion site in non-allodynia mice induced allodynia. The inhibition of P2X4 receptors in allodynia mice reduced allodynia. These results suggest that an excess buildup of intracellular ATP in the resting state causes at-level NP-SCI as a result of the extracellular release of ATP with mechanical stimulation.

Original languageEnglish
Article number483
JournalCellular and Molecular Life Sciences
Issue number9
Publication statusPublished - Sept 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology


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