Contribution of Spinal Cord mTORC1 to Chronic Opioid Tolerance and Hyperalgesia

Morphine and related opiates are commonly used in the clinical treatment of various types of moderate to severe pain. However, this treatment is often limited by a rapid development of opiate tolerance and hyperalgesia. A number of studies reported that mammalian target of rapamycin (mTOR), an enzyme that controls most protein translation, is required for the genesis of opioid tolerance and hyperalgesia. Repeated intrathecal morphine injections activated spinal dorsal horn mTOR through μ opioid receptor-triggered PI3K/Akt signaling. The resulting increase in mTOR activation led to an increase in translation initiation activity and nascent protein synthesis. Blocking this activation either by the specific mTOR inhibitor rapamycin or specific mTOR siRNA attenuated the development and maintenance of morphine analgesic tolerance and hyperalgesia. Mimicking this increase decreased morphine analgesia and produced pain hypersensitivity. These findings identify mTOR as a likely target for treatment of chronic opioid tolerance and hyperalgesia.