Involvement of the spinal NMDA receptor/PKCγ signaling pathway in the development of bone cancer pain

N-methyl-d-aspartate (NMDA) receptor and protein kinase C (PKC) play important roles in the induction and maintenance of central sensitization during pain states. It has been shown that spinal NMDA receptor-dependent activation of PKCγ facilitates nociception during neuropathic and inflammatory pain, but its involvement in bone cancer pain has not previously been established. The aim of this study was to examine the potential role of the spinal NMDA receptor/PKCγ signaling pathway in the development of bone cancer pain. Osteosarcoma NCTC 2472 cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce ongoing bone cancer-related pain behaviors. At day 7, 10 and 14 after operation, the expression of PKCγ mRNA in the spinal cord was higher in tumor-bearing mice compared to the sham mice. At day 14, intrathecal administration of 5 μg of NR2B subunit-specific NMDA receptor antagonist ifenprodil attenuated the up-regulation of PKCγ mRNA in the spinal cord as well as bone cancer-evoked thermal hyperalgesia and mechanical allodynia. Furthermore, intrathecal injection of 10 μg of PKC inhibitor H-7 attenuated cancer-evoked thermal hyperalgesia and mechanical allodynia at day 14. These results suggest that the NMDA receptor/PKCγ signaling pathway may participate in the development of bone cancer pain, and ifenprodil may be a useful alternative or adjunct therapy for bone cancer pain.