MTOR Promotes Astrocyte Activation and Participates in Neuropathic Pain through an Upregulation of RIP3

Neurochemical Research, 2025 · DOI: https://doi.org/10.1007/s11064-025-04341-x · Published: January 16, 2025

Simple Explanation

Neuropathic pain (NP) results from abnormalities in pain pathways. This study found increased mTOR in astrocytes and astrocyte activation in the spinal cord following chronic constriction injury (CCI). Inhibiting mTOR reversed CCI-induced hyperalgesia and neuroinflammation. Overexpression of mTOR led to an upregulation of RIP3, and inhibiting RIP3 eliminated mTOR-induced astrocyte activation. mTOR controls RIP3 expression in astrocytes through ITCH-mediated ubiquitination and autophagy-dependent degradation. The study reveals a link between mTOR and RIP3 in promoting astrocyte activation.

Study Duration

Not specified

Participants

Adult male Wistar rats weighing 150–180 g

Evidence Level

Not specified

Key Findings

1
mTOR is activated in astrocytes within the spinal cord following chronic constriction injury (CCI), contributing to neuropathic pain.
2
Pharmacological inhibition or knockdown of mTOR in astrocytes alleviates CCI-induced hyperalgesia and neuroinflammation.
3
mTOR regulates RIP3 expression in astrocytes through ITCH-mediated ubiquitination and autophagy-dependent degradation, promoting astrocyte activation.

Research Summary

This study investigates the mechanisms underlying neuropathic pain (NP), focusing on the role of mTOR in astrocytes. It finds that mTOR is activated in astrocytes following chronic constriction injury (CCI), contributing to NP. The research demonstrates that inhibiting mTOR alleviates CCI-induced hyperalgesia and neuroinflammation. Overexpression of mTOR upregulates RIP3, and inhibiting RIP3 eliminates mTOR-induced astrocyte activation. The study uncovers a link between mTOR and RIP3 in promoting astrocyte activation. mTOR controls RIP3 expression via ITCH-mediated ubiquitination and autophagy-dependent degradation, offering potential therapeutic targets for NP.

Practical Implications

Therapeutic Target Identification

mTOR and RIP3 may serve as potential targets for the treatment of neuropathic pain.

Personalized Treatment Protocols

Targeting the mTOR-RIP3 pathway has the potential for development of highly effective and safe personalized treatment protocols.

Astrocytic-Neuronal Communication Pathway

mTOR-driven pain may involve an astrocytic-neuronal communication pathway, revealing the potential for the development of novel therapeutic targets.

Study Limitations

1
The study only used male rats, and sex differences in pain mechanisms were not investigated.
2
The study did not investigate the long-term effects of mTOR or RIP3 inhibition.
3
The exact mechanisms underlying the relationship between ITCH and mTOR remain to be elucidated.

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