Abstract
Neuropathic pain (NP), a chronic pain condition, is mostly the result of astrocyte activation within the spinal cord. Here, we investigated the underlying mechanisms associated with this effect. We found that following chronic constriction injury (CCI) surgery, there was an increase of mTOR in astrocytes and an activation of astrocytes within the spinal cords. Overexpressing mTOR by intrathecal injection of TSC2-shRNA further promoted CCI-induced neuroinflammation and astrocyte activation. Knockdown of astrocytic mTOR reversed hyperalgesia and rescued the downregulation of spinal glutamate metabolism-related protein expression. Interestingly, overexpression of mTOR resulted in the RIP3 up-regulation, and pharmacological inhibition of RIP3 eliminated the mTOR-induced astrocyte activation. Mechanistically, we found that mTOR controlled the expression of RIP3 in astrocytes through ITCH-mediated ubiquitination and an autophagy-dependent degradation. Taken together, our results reveal an unanticipated link between mTOR and RIP3 in promoting astrocyte activation, providing new avenues of investigation directed toward the management and treatment of NP.