Opioid receptor–triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia
Ji-Tian Xu, … , Myron Yaster, Yuan-Xiang Tao
Ji-Tian Xu, … , Myron Yaster, Yuan-Xiang Tao
Published January 2, 2014
Citation Information: J Clin Invest. 2014;124(2):592-603. https://doi.org/10.1172/JCI70236.
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Research Article Neuroscience

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

Abstract

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 μ 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 μ 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.

Authors

Ji-Tian Xu, Jian-Yuan Zhao, Xiuli Zhao, Davinna Ligons, Vinod Tiwari, Fidelis E. Atianjoh, Chun-Yi Lee, Lingli Liang, Weidong Zang, Dolores Njoku, Srinivasa N. Raja, Myron Yaster, Yuan-Xiang Tao

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Figure 4

Morphine-induced activation of the mTOR pathway is ε opioid receptor dependent in dorsal horn neurons during chronic morphine exposure.

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Morphine-induced activation of the mTOR pathway is ε opioid receptor dep...
(A and B) Naltrexone (Nal, 100 εM; A) and CTOP (CT, 10 εM; B) blocked morphine-induced (20 εM) increases in p-mTOR, p-S6K1, and p–4E-BP1 in cultured dorsal horn neurons. *P < 0.05, **P < 0.01 vs. control (C); ##P < 0.01 vs. morphine. n = 4–5 repeats per group. (C) CTOP (10 εM) blocked DAMGO-induced (DA, 20 εM) increases in p-mTOR, p-S6K1, and p–4E-BP1 in cultured dorsal horn neurons. **P < 0.01 vs. control; ##P < 0.01 vs. DAMGO. n = 4–5 repeats per group. (D) Coinjection of CTOP (1 ng) blocked morphine-induced (10 εg) increases in p-mTOR, p-S6K1, and p–4E-BP1 in dorsal horn on day 7 of twice-daily intrathecal morphine injections. **P < 0.01 vs. saline plus vehicle; #P < 0.05, ##P < 0.01 vs. morphine plus vehicle. n = 5 rats per group. (E) Subcutaneous injection of morphine (20 mg/kg, twice daily for 5 days) increased the level of dorsal horn p-mTOR in wild-type mice, but not in ε opioid receptor knockout mice. *P < 0.05 vs. saline-treated wild-type. n = 4 mice per group. (F) Colocalization (arrows) of ε opioid receptor (MOR) mRNA with mTOR and p-mTOR in dorsal horn neurons on day 7 of twice-daily intrathecal morphine injections. Scale bar: 50 εm.