It has been reported that remarkable and sustained activation of astrocytes and/or microglia occurs in cancer induced pain (CIP), which is different from neuropathic and inflammatory pain. The present study was designed to investigate the role of spinal Toll-like receptor 4 (TLR4) induced glial neuroinflammation in cancer induced pain using a modified rat model of bone cancer. The rat model of CIP consisted of unilateral intra-tibial injection with Walker 256 mammary gland carcinoma. Nine days after Walker 256 inoculation, a robust activation of both astrocytes and microglia in bilateral spinal dorsal horn was observed together with significant bilateral mechanical allodynia. This neuroinflammation was characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker), and an elevated level of IL-1β, IL-6 and TNF-α mRNA. I.t. administration of fluorocitrate (an inhibitor of glial metabolism, 1 nmol) or minocycline (an inhibitor of microglia, 100 μg) has significant anti-allodynic effects on day 12 after Walker 256 inoculation. Naloxone (a nonstereoselective TLR4 signaling blocker, 60 μg, i.t.) also significantly alleviated mechanical allodynia and simultaneously blocked the increased inflammatory cytokine mRNA. The results suggested that spinal TLR4 might play an important role in the sustained glial activation that critically contributed to the robust and sustained spinal neuroinflammation in CIP. This result could potentially help clinicians and researchers to better understand the mechanism of complicated cancer pain.
BackgroundThe most frequent pain in patients with metastatic breast and prostate cancer is bone pain, which can be severe and difficult to treat. The mechanisms underlying this pain remain unclear. Here we investigated the role of c-jun N-terminal kinase (JNK) pathway in the spinal cord in cancer-induced bone pain (CIBP).ResultsIn this study, we used an established rat CIBP model to investigate the possible role of JNK activation in the spinal cord. After intra-tibial inoculation with Walker 256 rat mammary gland carcinoma cells, the rats displayed mechanical allodynia on day 5, which lasted to day 16. The activation of JNK in neurons and astrocytes in the spinal cord was found on day 12 and day 16 after intra-tibial inoculation with carcinoma cells. A single intrathecal injection with JNK inhibitor SP600125 by lumbar puncture attenuated mechanical allodynia on day 12, and repeated intrathecal injection of SP600126 from day 10 to day 14 had a cumulative analgesic effect on CIBP.ConclusionsTaken together, our results demonstrated for the first time that JNK activation in the spinal cord is required in the maintenance of CIBP. Inhibition of the spinal JNK pathway may provide a new therapy for CIBP management.
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