Systemic Rapamycin Attenuates Morphine-Induced Analgesic Tolerance and Hyperalgesia in Mice

Previous studies showed that repeated intrathecal morphine injection activated the mammalian target of rapamycin complex 1 (mTORC1) in spinal dorsal horn neurons and that blocking this activation by intrathecal infusion of rapamycin, a specific mTORC1 inhibitor, prevented the initiation of morphine-induced tolerance and hyperalgesia. However, in clinic, rapamycin is usually administrated orally. In this study, we examined whether systemic administration of rapamycin had the effect on morphine-induced tolerance and hyperalgesia in mice. Repeatedly intraperitoneal injection of morphine led to morphine analgesic tolerance on day 5 post-injection evidenced by a marked decrease in morphine's maximal possible analgesic effect and hyperalgesia on day 6 post-injection demonstrated by significant increases in paw withdrawal frequency in response to mechanical stimulation and decreases in paw withdrawal latency in response to cold stimulation on bilateral sides. Co-intraperitoneal injection with rapamycin prevented the development of morphine analgesic tolerance and hyperalgesia. Moreover, on day 6 after morphine injection, co-intraperitoneal injection with rapamycin reduced the established morphine tolerance and hyperalgesia. Co-intraperitoneal injection of rapamycin also attenuated the morphine-induced increases in the levels of phosphorylated mTOR and its downstream target phosphorylated 4E-BP1 in the spinal cord dorsal horn. Our findings indicate that, like intrathecal injection, systemic administration of rapamycin has significant effects on both induction and maintenance of morphine tolerance and hyperalgesia. Systemic mTOR inhibitors could serve as promising medications for use as adjuvants with opioids in clinical chronic pain management.