Granulocyte colony stimulating factor (GCSF) treatment in neuropathic pain

Abstract

<p>Granulocyte colony stimulating factor (GCSF) is an endogenous growth factor that can stimulate granulocyte formation and is used widely in hematogenous disease without significant clinical side effects. Several clinical and animal studies had showed that both a single high-dose and repeated low-dose systemic GCSF treatment can attenuate neuropathic pain after central or peripheral nerve injury. GCSF treatment can recruit more opioid containing neutrophils to injured tissue, up-regulate opioid receptors (mu opioid receptor) on the injured nerve, which decreased nociceptive signals from injured nerve to the spinal dorsal horn. Thereafter, activated microglia, increased phosphorylated-p38 (p-p38) and pro-inflammatory cytokines on the spinal dorsal horn are suppressed, which further attenuated neuropathic pain. The systemic GCSF administration may avoid the addiction side effect induced by repeated exogenous opioid exposure and provide a new therapeutic strategy to treat neuropathic pain.</p>

Interactions between Autophagy, Proinflammatory Cytokines, and Apoptosis in Neuropathic Pain: Granulocyte Colony Stimulating Factor as a Multipotent Therapy in Rats with Chronic Constriction Injury

“…In contrast, an increase in autophagic activity in the early phase before proinflammatory cytokines reach the threshold level and induce neuropathic pain can effectively alleviate pain development. This is consistent with our findings that vehicle-treated CCI rats also exhibited increased autophagic activity on the 3rd day after nerve injury but showed increases in proinflammatory cytokine/chemokine (IL-6, TNF-α, and MCP-1) levels in the DRG from the 2nd to 7th days [1,5] after nerve injury, which occurred before autophagic activity increased.…”

“…Previous studies, including ours, have shown that granulocyte colony-stimulating factor (G-CSF) treatment can attenuate neuropathic pain in rats with chronic constriction injury (CCI) and spinal cord injury [1][2][3][4][5]. Human clinical trials have also demonstrated the analgesic effects of G-CSF in patients with compressive myelopathy [6,7].…”

“…The underlying mechanisms by which autophagy regulates neuropathic pain are complex interactions between many proinflammatory cytokines [46]. Our previous studies showed that G-CSF can abrogate the increased proinflammatory cytokine (IL-6 and TNF-α) and chemokine (MCP-1) levels in the DRG from the 2nd to 6th day and 7th day after nerve injury, respectively [1,5]. Previous studies have also shown that autophagy can suppress proinflammatory cytokine activity [23,[46][47][48].…”

“…Each animal was allowed 10 min for habituation before the behavior tests. We tested mechanical allodynia using the von Frey hair test according to a previously described protocol [1,2,5]. We applied von Frey hairs to the central region of the right plantar surface of the hind paw in ascending order of force (1.4, 2.0, 4, 6, 8, 10, 15, and 26 g).…”

“…Human clinical trials have also demonstrated the analgesic effects of G-CSF in patients with compressive myelopathy [6,7]. Previous studies have reported that G-CSF treatment recruits opioid-containing polymorphonuclear granulocytes (PMNs), upregulates Mu opioid receptors (MORs) on injured nerves, suppresses proinflammatory cytokines (Interleukin-6 [IL-6], Tumor Necrosis Factor-α [TNF-α] and monocyte chemoattractant protein-1 [MCP-1]) in dorsal root ganglia (DRG) neurons and downregulates phosphorylated p38 and microglial activity in the spinal dorsal horn, thus attenuating neuropathic pain in CCI rats [1][2][3][4][5]. G-CSF is a type of multipotent cytokine that increases the circulating progenitor cells of multiple hematopoietic lineages and interacts with multiple cytokines [8].…”