Spinal cord NMDA receptor-mediated activation of mammalian target of rapamycin is required for the development and maintenance of bone cancer-induced pain hypersensitivities in rats

Mammalian target of rapamycin (mTOR) controls mRNA translation and is critical for neuronal plasticity. However, how it participates in central sensitization underlying chronic pain is unclear. Here, we show that NMDA receptors are required for the functional role of spinal cord mTOR in bone cancer pain induced by injecting prostate cancer cells (PCCs) into the tibia. Intrathecal rapamycin, a specific mTOR inhibitor, dose dependently attenuated the development and maintenance of PCC-induced mechanical allodynia and thermal hyperalgesia. Rapamycin alone did not affect locomotor activity and acute responses to thermal or mechanical stimuli. Phosphorylation of mTOR and p70S6K (a downstream effector) was increased time dependently in L_4-5 dorsal horn and transiently in L_4-5 dorsal root ganglions on the ipsilateral side after PCC injection, although total expression of mTOR or p70S6K was not changed in these regions. The increases in dorsal horn were abolished by intrathecal infusion of DL-AP5, an NMDA receptor antagonist. Moreover, NMDA receptor subunit NR1 colocalized with mTOR and p70S6K in dorsal horn neurons. These findings suggest that PCC-induced dorsal horn activation of the mTOR pathway participates in NMDA receptor-triggered dorsal central sensitization under cancer pain conditions. Perspective: The present study shows that inhibition of spinal mTOR blocks cancer-related pain without affecting acute pain and locomotor function. Given that mTOR inhibitors are FDA-approved drugs, mTOR in spinal cord may represent a potential new target for preventing and/or treating cancer-related pain.