In particular, we found that G-CSF can alleviate neuropathic pain, at least through the following mechanisms: (1) G-CSF increases circulating and peripheral PMN cells, which are the main opioid-containing leukocytes, in early inflammation; (2) under early inflammatory conditions, the recruited PMN cells secrete opioid peptides that bind to opioid receptors on peripheral sensory neurons to mediate antinociception (Cabot et al., 1997, Binder et al., 2004, Mousa et al., 2004, Rittner et al., 2006b, Leanez et al., 2009); (3) G-CSF inhibits inflammatory cytokines that contribute to inflammatory pain; and (4) G-CSF significantly decreases microglial cell activation in the spinal DH compared to vehicle treatment. This is the first study demonstrating that G-CSF is effective in alleviating thermal hyperalgesia and mechanical allodynia in an animal model of chronic pain. Consequently, our research may introduce a new method of treating chronic neuropathic pain.
In addition, microglial activation of the spinal DH is directly related with central sensitization, and closely correlated with nociceptive behavior in early inflammatory stage. Both of G-CSF and indomethacin attenuate microglial activation and production of pro-inflammatory cytokine, respectively; this suggests that microglia closely associate with central sensitization and neuroinflammation. The treatment of severe pain with opioids is limited by their undesirable central side effects. This study shows that exogenously applied recombinant human G-CSF is a promising new therapeutic avenue for treating neuropathic pain by
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providing opioid analgesics that act outside the central nervous system, targeting opioid peptide-containing immune cells to injured peripheral nerves, and enhancing opioid production at the sites of injury while not being hampered by side effects such as exogenesis or opioid-induced addiction. In contrast, the results presented here indicate that Nogo-A plays an important role in CNS injury-induced IL-1β release. By inhibiting Nogo-A expression, the systemic delivery of indomethacin can greatly ameliorate the TBI-induced pro-inflammatory cytokine overload.
These results suggest that the neuroprotective activity of indomethacin is mediated by the repression of Nogo-A expression in the early stages of the process.
Because systemic administration of G-CSF had a positive effect on behavioral outcome and histopathological assessment after spinal cord injury rats (Urdzikova et al., 2006) and does not increase posttraumatic brain edema at 24 h in TBI rats (Whalen et al., 2000) , it is highly possible that G-CSF-mobilized PMN cell play a beneficial role of treating TBI-induced neuroinflammation. In the other words, nociception-induced c-Fos protein expression in the spinal DH neurons is suppressed by local administration of indomethacin (Honore et al., 1995), it showed that indomethacin could ameliorate peripheral nerve injury induced neuropathic pain and central sensitization. However, further study is needed to verify and delineate these complex mechanisms.
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