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.
Highlights
During nerve injury, pain is associated with release of proinflammatory cytokines such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6, which are essential for establishing nociceptive processing [1,2]
Post-constriction injury (CCI) thermal hyperalgesia and mechanical allodynia were not altered by the infusion of the vehicle; in contrast, CCI rats with i.v. injection of Granulocyte colony-stimulating factor (G-CSF) exhibited significantly attenuated thermal hyperalgesia and mechanical allodynia compared to the rats treated with the vehicle (p,0.01) (Fig. 1A, B)
The major finding of this study is that exogenously applied GCSF is effective in alleviating thermal hyperalgesia and mechanical allodynia in rats with CCI mainly through the activation of leukocyte-derived endogenous opioid secretion, downregulation of IL-6 and tumor necrosis factor-a (TNF-a) inflammatory cytokines, and decreased microglial cell activation in the spinal dorsal horn
Summary
Pain is associated with release of proinflammatory cytokines such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6, which are essential for establishing nociceptive processing [1,2]. The attenuation of proinflammatory cytokines alleviates neuropathic pain. Clinical exogenous opioid administration is associated with several side effects in addition to tolerance development because of their central mechanisms of action, limiting their use [5]. To overcome these limitations, endogenous opioid-mediated antinociception has been extensively studied, and its physiological and clinical relevance have been established [6]
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