Opioid receptor–triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia
| Autor: | Vinod Tiwari, Weidong Zang, Myron Yaster, Lingli Liang, Srinivasa N. Raja, Davinna Ligons, Jian-Yuan Zhao, Xiuli Zhao, Dolores B. Njoku, Ji Tian Xu, Chun Yi Lee, Fidelis E. Atianjoh, Yuan Xiang Tao |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Time Factors medicine.drug_class Analgesic Receptors Opioid mu Pain mTORC1 Mechanistic Target of Rapamycin Complex 1 Pharmacology Rats Sprague-Dawley Phosphatidylinositol 3-Kinases Opioid receptor medicine Animals Pain Management Protein kinase B Injections Spinal PI3K/AKT/mTOR pathway Cell Proliferation Neurons Sirolimus Dose-Response Relationship Drug Morphine business.industry TOR Serine-Threonine Kinases Chronic pain Drug Tolerance General Medicine medicine.disease Rats Spinal Cord Opioid Hyperalgesia Multiprotein Complexes medicine.symptom business Spleen Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 124:592-603 |
| ISSN: | 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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