2. Academic Validation
  3. Excess intracellular ATP causes neuropathic pain following spinal cord injury

Excess intracellular ATP causes neuropathic pain following spinal cord injury

  • Cell Mol Life Sci. 2022 Aug 16;79(9):483. doi: 10.1007/s00018-022-04510-z.
Nobuhiko Nakajima  # 1,  Yuichiro Ohnishi  # 2 3,  Masamichi Yamamoto 4,  Daiki Setoyama 5,  Hirohiko Imai 6,  Tomofumi Takenaka 1,  Mari Matsumoto 7,  Koichi Hosomi 1 8,  Yoichi Saitoh 8,  Hidemasa Furue 9,  Haruhiko Kishima 1
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
  • 2 Department of Research Promotion and Management, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan. ohnishinsurg@gmail.com.
  • 3 Department of Neurosurgery, Osaka Gyoumeikan Hospital, Osaka, Japan. ohnishinsurg@gmail.com.
  • 4 Department of Research Promotion and Management, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan. yamamoto.mailserver@gmail.com.
  • 5 Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 6 Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, Japan.
  • 7 Department of Research Promotion and Management, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan.
  • 8 Department of Neuromodulation and Neurosurgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
  • 9 Department of Neurophysiology, Hyogo College of Medicine, Hyogo, Japan.
  • # Contributed equally.
PMID: 35972649 DOI: 10.1007/s00018-022-04510-z
Abstract

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.

Keywords

Astrocyte; Microglia; Neuroinflammation; Neuropathic pain; Purinergic receptor.

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