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Chronic Constriction of the Sciatic Nerve and Pain Hypersensitivity Testing in Rats
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Persistent Rheb-induced mTORC1 activation in spinal cord neurons induces hypersensitivity in neuropathic pain

Xiaqing Ma1, Wenjie Du1, Wenying Wang1

  • 1Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.

Cell Death & Disease
|September 13, 2020
PubMed

Insights

Spinal Rheb activates mTORC1 signaling, contributing to neuropathic pain. Inhibiting this pathway with rapamycin alleviates pain and enhances morphine effectiveness, offering a new pain management strategy.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pain Research

Background:

  • The small GTPase Ras homolog enriched in the brain (Rheb) is a key activator of the mammalian target of rapamycin (mTOR) pathway.
  • mTOR signaling regulates crucial cellular processes including growth and cell cycle progression.
  • Neuropathic pain involves complex molecular alterations in the central nervous system.

Purpose of the Study:

  • To investigate the role of Rheb-mediated mTORC1 signaling in the development and maintenance of neuropathic pain.
  • To determine if targeting the Rheb-mTORC1 pathway can alleviate pain symptoms and improve existing pain therapies.

Main Methods:

  • Utilized a chronic constriction injury (CCI) model to induce neuropathic pain in rodents.
  • Assessed spinal Rheb expression and mTORC1 pathway activation (phosphorylation of mTOR, S6, 4-E-BP1) via Western blot and immunofluorescence.
  • Administered rapamycin to inhibit mTORC1 signaling and evaluated behavioral pain responses.
  • Performed ex vivo spinal slice electrophysiology to record neuronal activity.

Main Results:

  • CCI induced significant upregulation of spinal Rheb expression and activation of the mTORC1 pathway.
  • Rapamycin treatment alleviated neuropathic pain behaviors and restored morphine efficacy in CCI mice.
  • Immunofluorescence confirmed neuronal co-localization of Rheb and phosphorylated S6 (pS6) in the spinal cord.
  • Spinal slice recordings showed that CCI increased neuronal firing frequency, which was reversed by rapamycin.
  • Rheb knockin mice exhibited a behavioral phenotype similar to CCI.

Conclusions:

  • Spinal Rheb is induced during neuropathic pain and activates mTORC1 signaling.
  • The Rheb-mTORC1 pathway plays a critical role in regulating spinal sensitization in neuropathic pain.
  • Targeting the mTOR pathway presents a promising novel strategy for managing neuropathic pain.

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