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mTOR, a New Potential Target for Chronic Pain and Opioid-Induced Tolerance and Hyperalgesia

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Review

mTOR, a New Potential Target for Chronic Pain and Opioid-Induced Tolerance and Hyperalgesia

Brianna Marie Lutz et al. Mol Pain.

Abstract

Chronic pain is a major public health problem with limited treatment options. Opioids remain a routine treatment for chronic pain, but extended exposure to opioid therapy can produce opioid tolerance and hyperalgesia. Although the mechanisms underlying chronic pain, opioid-induced tolerance, and opioid-induced hyperalgesia remain to be uncovered, mammalian target of rapamycin (mTOR) is involved in these disorders. The mTOR complex 1 and its triggered protein translation are required for the initiation and maintenance of chronic pain (including cancer pain) and opioid-induced tolerance/hyperalgesia. Given that mTOR inhibitors are FDA-approved drugs and an mTOR inhibitor is approved for the treatment of several cancers, these findings suggest that mTOR inhibitors will likely have multiple clinical benefits, including anticancer, antinociception/anti-cancer pain, and antitolerance/hyperalgesia. This paper compares the role of mTOR complex 1 in chronic pain, opioid-induced tolerance, and opioid-induced hyperalgesia.

Figures

Fig. 1
Fig. 1
mTOR signaling pathway. Activated mTOR phosphorylates 4E-BP1/2 and S6K1/2. The phosphorylation of 4E-BP1/2 causes the release of eIF4E which is then free to combine with the translation initiation complex, resulting in increased protein translation. Phosphorylated S6K1 phosphorylates eIF4B and S6 which also lead to increased protein translation. 4E-BP1/2: eIF4E-binding protein1/2. 40S: an eukaryotic small ribosomal subunit. 60S: an eukaryotic large ribosomal subunit. eIF4E/B/G/A: eukaryotic translation initiation factor 4E/4B/4G/4A. mTOR: mammalian target of rapamycin. p: phosphorylated. S6K1/2, p70 ribosomal S6 Kinase 1/2
Fig. 2
Fig. 2
Proposed mechanism of spinal cord NMDA receptor-mediated activation of mTOR signaling in cancer pain. Under normal conditions (a), magnesium blocks NMDAR activity, thus silencing the intracellular kinases including the mTOR signaling pathway. Under cancer conditions (b), cancer-caused noxious insult leads to removal of the magnesium from NMDA receptors, resulting in calcium influx through NMDA receptor activation. The influx of calcium may then activate PI3K and Akt kinases which go on to phosphorylate mTOR. Active mTOR phosphorylates S6K1/2 and 4E-BP1/2 leading to protein translation initiation. 4E-BP1/2: eIF4E-binding protein1/2. Akt: protein kinase B. mTOR: mammalian target of rapamycin. NMDAR: NMDA receptor; NR1: a subunit of NMDA receptors. p: phosphorylated. PI3K: phosphoinositide 3-kinase. S6K1/2, p70 ribosomal S6 Kinase 1/2
Fig. 3
Fig. 3
Proposed model for the involvement of spinal cord mTOR in chronic opioid tolerance and hyperalgesia. Under normal conditions (a), mTOR is inactivated. 4E-BP1/2 binds to eIF4E, preventing its associations with the translation initiation complex, thus silencing protein translation. After repeated morphine exposure (b), activation of μ opioid receptors leads to the phosphorylation of PI3K and Akt, initiating a phosphorylation cascade including mTOR/S6K1/2/4E-BP1/2. eIF4E release, phosphorylated eIF4B, and phosphorylated S6 trigger protein translation. 4E-BP1/2: eIF4E-binding protein1/2. Akt: protein kinase B. eIF4E/eIF4B, eukaryotic translation initiation factor 4E/4B. mTOR: mammalian target of rapamycin. p: phosphorylated. PI3K: phosphoinositide 3-kinase. S6K1/2, p70 ribosomal S6 Kinase 1/2. S6K1, S6 Kinase 1. μ: μ opioid receptor

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