Stage-dependent anti-allodynic effects of intrathecal Toll-like receptor 4 antagonists in a rat model of cancer induced bone pain

It has been reported that Toll-like receptor 4 (TLR4), which plays an important role in glial activation in neuropathic pain, is significantly increased in cancer pain. The present study was designed to assess the role of TLR4 in cancer-induced bone pain (CIBP) by intrathecal administration of TLR4 signaling pathway blocker naloxone or lipopolysaccharide Rhodobacter sphaeroides (LPS-RS). The rats developed significant mechanical allodynia from day 8 after intratibial Walker 256 inoculation. Intrathecal injection of naloxone or LPS-RS at day 8 significantly attenuated mechanical allodynia as shown by increased paw withdrawal thresholds. In contrast, the same pharmacological treatment showed no or slight pain relieving effect at day 16. Our findings demonstrate that the spinal TLR4 signaling pathway contributes to the mechanism underlying CIBP in a stage-dependent manner in rats, and it may be an efficacious target at early stage for the treatment in the future.