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Opioid receptor-triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia.

Authors: Xu, JT  Zhao, JY  Zhao, X  Ligons, D  Tiwari, V  Atianjoh, FE  Lee, CY  Liang, L  Zang, W  Njoku, D  Raja, SN  Yaster, M  Tao, YX 
Citation: Xu JT, etal., J Clin Invest. 2014 Feb;124(2):592-603. doi: 10.1172/JCI70236. Epub 2014 Jan 2.
Pubmed: (View Article at PubMed) PMID:24382350
DOI: Full-text: DOI:10.1172/JCI70236

The development of opioid-induced analgesic tolerance and hyperalgesia is a clinical challenge for managing chronic pain. Adaptive changes in protein translation in the nervous system are thought to promote opioid tolerance and hyperalgesia; however, how opioids drive such changes remains elusive. Here, we report that mammalian target of rapamycin (mTOR), which governs most protein translation, was activated in rat spinal dorsal horn neurons after repeated intrathecal morphine injections. Activation was triggered through mu opioid receptor and mediated by intracellular PI3K/Akt. Spinal mTOR inhibition blocked both induction and maintenance of morphine tolerance and hyperalgesia, without affecting basal pain perception or locomotor functions. These effects were attributed to the attenuation of morphine-induced increases in translation initiation activity, nascent protein synthesis, and expression of some known key tolerance-associated proteins, including neuronal NOS (nNOS), in dorsal horn. Moreover, elevating spinal mTOR activity by knocking down the mTOR-negative regulator TSC2 reduced morphine analgesia, produced pain hypersensitivity, and increased spinal nNOS expression. Our findings implicate the mu opioid receptor-triggered PI3K/Akt/mTOR pathway in promoting morphine-induced spinal protein translation changes and associated morphine tolerance and hyperalgesia. These data suggest that mTOR inhibitors could be explored for prevention and/or reduction of opioid tolerance in chronic pain management.

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CRRD Object Information
CRRD ID: 10040983
Created: 2015-05-07
Species: All species
Last Modified: 2015-05-07
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.