Early systemic granulocyte-colony stimulating factor treatment attenuates neuropathic pain after peripheral nerve injury

Po Kuan Chao, Kwok Tung Lu, Yun Lin Lee, Jin Chung Chen, Hung Li Wang, Yi Ling Yang, Mei Yun Cheng, Ming Feng Liao, Long Sun Ro

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Abstract

Recent studies have shown that opioid treatment can reduce pro-inflammatory cytokine production and counteract various neuropathic pain syndromes. Granulocyte colony-stimulating factor (G-CSF) can promote immune cell differentiation by increasing leukocytes (mainly opioid-containing polymorphonuclear (PMN) cells), suggesting a potential beneficial role in treating chronic pain. This study shows the effectiveness of exogenous G-CSF treatment (200 μg/kg) for alleviating thermal hyperalgesia and mechanical allodynia in rats with chronic constriction injury (CCI), during post-operative days 1-25, compared to that of vehicle treatment. G-CSF also increases the recruitment of opioid-containing PMN cells into the injured nerve. After CCI, single administration of G-CSF on days 0, 1, and 2, but not on day 3, relieved thermal hyperalgesia, which indicated that its effect on neuropathic pain had a therapeutic window of 0-48 h after nerve injury. CCI led to an increase in the levels of interleukin-6 (IL-6) mRNA and tumor necrosis factor-α (TNF-α) protein in the dorsal root ganglia (DRG). These high levels of IL-6 mRNA and TNF-α were suppressed by a single administration of G-CSF 48-144 h and 72-144 h after CCI, respectively. Furthermore, G-CSF administered 72-144 h after CCI suppressed the CCI-induced upregulation of microglial activation in the ipsilateral spinal dorsal horn, which is essential for sensing neuropathic pain. Moreover, the opioid receptor antagonist naloxone methiodide (NLXM) reversed G-CSF-induced antinociception 3 days after CCI, suggesting that G-CSF alleviates hyperalgesia via opioid/opioid receptor interactions. These results suggest that an early single systemic injection of G-CSF alleviates neuropathic pain via activation of PMN cell-derived endogenous opioid secretion to activate opioid receptors in the injured nerve, downregulate IL-6 and TNF-α inflammatory cytokines, and attenuate microglial activation in the spinal dorsal horn. This indicates that G-CSF treatment can suppress early inflammation and prevent the subsequent development of neuropathic pain.

Original languageEnglish
Article numbere43680
JournalPloS one
Volume7
Issue number8
DOIs
Publication statusPublished - 2012 Aug 24

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Chao, P. K., Lu, K. T., Lee, Y. L., Chen, J. C., Wang, H. L., Yang, Y. L., Cheng, M. Y., Liao, M. F., & Ro, L. S. (2012). Early systemic granulocyte-colony stimulating factor treatment attenuates neuropathic pain after peripheral nerve injury. PloS one, 7(8), [e43680]. https://doi.org/10.1371/journal.pone.0043680