Blocking mammalian target of rapamycin alleviates bone cancer pain and morphine tolerance via µ-opioid receptor

Int J Cancer. 2016 Apr 15;138(8):2013-20. doi: 10.1002/ijc.29927. Epub 2015 Dec 8.


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 Cɛ (PKCɛ)/protein kinase A (PKA) induced by morphine and further extended analgesia of morphine via µ-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 PKCɛ/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.

Keywords: bone cancer; mTOR; morphine tolerance; neuropathic pain.

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Animals
  • Blotting, Western
  • Bone Neoplasms / complications*
  • Disease Models, Animal
  • Drug Tolerance / physiology*
  • Morphine / pharmacology
  • Pain / metabolism*
  • Rats
  • Rats, Wistar
  • Receptors, Opioid, mu / metabolism*
  • Signal Transduction / physiology
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*


  • Analgesics, Opioid
  • Receptors, Opioid, mu
  • Morphine
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Sirolimus