Blocking Mammalian Target Of Rapamycin Alleviates Bone Cancer Pain And Morphine Tolerance Via Mu-Opioid Receptor

The current study was to examine the underlying mechanisms responsible for the role of mammalian target of rapamycin (mTOR) in regulating bone cancer-evoked pain and the tolerance of systemic morphine. Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats and this evoked significant mechanical and thermal hyperalgesia. Our results showed that the protein expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1), p70 ribosomal S6 protein kinase 1 (S6K1) as well as phosphatidylinositide 3-kinase (p-PI3K) pathways were amplified in the superficial dorsal horn of the spinal cord of bone cancer rats compared with control rats. Blocking spinal mTOR by using rapamycin significantly attenuated activities of PI3K signaling pathways as well as mechanical and thermal hyperalgesia. Additionally, rapamycin enhanced attenuations of protein kinase C (PKC)/protein kinase A (PKA) induced by morphine and further extended analgesia of morphine via mu-opioid receptor (MOR). Our data for the first time revealed specific signaling pathways leading to bone cancer pain, including the activation of mTOR and PI3K and downstream PKC/PKA, and resultant sensitization of MOR. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of bone cancer pain often observed in clinics.What's new? Bone metastases cause localized breakthrough pain, but they can also increase a patient's overall sensitivity to pain. Treatment options for bone-cancer pain have been limited, in part because the underlying mechanisms of pain are poorly understood. In this study in mice, the authors found that when mTOR signaling pathways in the spine were blocked with rapamycin, pain sensitivity decreased. In addition, morphine tolerance was reduced. The study also identified specific molecular signaling pathways, which suggest potential new therapeutic targets for bone-cancer pain.