Abstract
Our previous animal studies and several human clinical trials have shown that granulocyte-colony stimulating factor (GCSF) can attenuate neuropathic pain through various mechanisms. GCSF itself is also a multipotent cytokine that can modulate microribonucleic acid (microRNA) expression profiles in vitro. In this study, we used the NanoString nCounter analysis system to screen the expression of different rodent microRNAs at early stage after nerve injury and studied the expression of related cytokines/chemokines in the dorsal root ganglia (DRGs) of rats that underwent chronic constriction injury (CCI) to explore the underlying mechanisms of the analgesic effects of GCSF. We found that microRNA-122 expression was downregulated by CCI; in contrast, GCSF treatment significantly upregulated microRNA-122 expression in the DRGs of CCI rats on the 1st day after nerve injury. We further studied the expression of different cytokines/chemokines (IL-1β, IL-6, and monocyte chemoattractant protein-1 (MCP-1)) that were modulated by microRNA-122. MCP-1 has been reported to participate in neuropathic pain development, and its expression on the DRGs of vehicle-treated CCI rats was significantly higher than that on the DRGs of sham-operated rats; in contrast, GCSF-treated rats exhibited significantly lower MCP-1 expression in the DRG than vehicle-treated rats on the 7th day after nerve injury. An early GCSF treatment can suppress MCP-1 expressions, through upregulating microRNA-122 expressions in the DRGs of CCI rats at an earlier stage, thus indirectly attenuating neuropathic pain development.
Highlights
Our previous animal studies and several similar studies have shown that granulocyte colony stimulating factor (GCSF) treatment can attenuate neuropathic pain in rats that undergo chronic constriction injury (CCI) and spinal cord injury [1,2,3,4]
We further examined the expression of different cytokines/chemokines (IL-1β, IL-6, and monocyte chemoattractant protein-1 [MCP-1]) that were modulated by microRNA-122 [34] in the DRGs of the various treatment groups at different time points to investigate the mechanisms underlying the analgesic effect of granulocyte-colony stimulating factor (GCSF)
Our study showed that microRNA-122 expression was decreased in the DRGs of CCI rats; in contrast, GCSF treatment upregulated microRNA-122 expression in the DRGs in the early stage after nerve injury
Summary
Our previous animal studies and several similar studies have shown that granulocyte colony stimulating factor (GCSF) treatment can attenuate neuropathic pain in rats that undergo chronic constriction injury (CCI) and spinal cord injury [1,2,3,4]. GCSF treatment was shown to recruit opioid-containing polymorphonuclear granulocytes (PMNs) to the injury site from 12 to 48 h after nerve injury, upregulate mu opioid receptor (MOR) expression on the injured nerve on days 1–3 after nerve injury, suppress proinflammatory cytokines (IL-6 and TNF-α) in the dorsal root ganglia (DRGs) on days 2–6 after nerve injury, downregulate phosphorylated p38 on day 3 after nerve injury and activated microglia on days 3–6 after nerve injury in the spinal dorsal horn, decrease IL-6 (pro-inflammatory cytokine) but increased IL-4 (anti-inflammatory cytokine) levels from days 1 to 7 in the spinal dorsal horn (SDH) after nerve injury and attenuate neuropathic pain development in CCI rats [1,2] (Figure 1). Nerve injury [1,2]. (↑: increase, ↓: decrease)
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