*Department of Orthopedic Surgery, Chiba Medical Center, Chiba, Japan †Graduate School of Medicine, Chiba University, Chiba Medical Center, Chiba, Japan ‡Chiba Aoba Municipal Hospital, Chiba Medical Center, Chiba, Japan; and §Department of Orthopedic Surgery, University of Tsukuba, Ibaraki, Japan.
Spine (Phila Pa 1976). 2014 Feb 1;39(3):192-7. doi: 10.1097/BRS.0000000000000108.
Animal experimental study with intervention.
The aim of this study was to elucidate therapeutic effects of delayed granulocyte colony-stimulating factor treatment for mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in rats.
Granulocyte colony-stimulating factor (G-CSF) is used clinically for patients with hematological disorders. Previous reports showed that immediate G-CSF attenuates neuropathic pain in CCI of the sciatic nerve. However, the acute treatment for neuropathic pain prior to accurate diagnosis is not realistic in clinical settings.
Adult, female Sprague-Dawley rats were subjected to the CCI model. This model induces mechanical allodynia on the ipsilateral hind paw within the first week after the injury. One week after CCI, rats received intraperitoneal G-CSF (15.0 μg/kg) for 5 consecutive days. Mechanical allodynia was assessed using the von Frey hair test. Immunohistochemistry for phosphorylated p38 mitogen-activated kinase (p-p38MAPK) and OX-42 (a marker for activated microglia) on tissue slides from a subset of rats 2 weeks after surgery. Western blot analyses were carried out to determine protein expression level of p-p38MAPK and interleukin-1 β on spinal cord homogenates 2 weeks after CCI.
Results of the von Frey filament test showed that G-CSF significantly attenuates mechanical allodynia induced by the CCI model. Immunohistochemistry revealed that G-CSF reduced the number of p-p38MAPK-positive cells in the ipsilateral dorsal horn compared with that in the vehicle group rats. Immunofluorescent double staining revealed that p-p38MAPK-expressing cells in the spinal cord dorsal horn are mainly microglia. Western blot analysis indicated that G-CSF decreased the expression levels of both p-p38MAPK and interleukin-1 β in the ipsilateral dorsal horn compared with that in the vehicle group rats.
The present results indicate a beneficial effect of delayed G-CSF treatment in an animal model of peripheral nerve injury-induced neuropathic pain.
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干预性动物实验研究。
本研究旨在阐明粒细胞集落刺激因子（G-CSF）延迟治疗对大鼠慢性坐骨神经缩窄损伤（CCI）所致机械性痛觉过敏的治疗作用。
G-CSF 临床上用于治疗血液系统疾病患者。先前的报告表明，即刻 G-CSF 可减轻CCI 所致的神经病理性疼痛。然而，在临床环境中，在准确诊断之前对神经病理性疼痛进行急性治疗是不现实的。
成年雌性 Sprague-Dawley 大鼠接受 CCI 模型。该模型在损伤后第一周内引起对侧后爪的机械性痛觉过敏。CCI 后 1 周，大鼠连续 5 天腹腔内给予 G-CSF（15.0 μg/kg）。使用 von Frey 毛发试验评估机械性痛觉过敏。在手术后 2 周，对部分大鼠的组织切片进行磷酸化 p38 丝裂原活化激酶（p-p38MAPK）和 OX-42（激活小胶质细胞的标志物）的免疫组织化学染色。在 CCI 后 2 周，通过 Western blot 分析确定脊髓匀浆中 p-p38MAPK 和白细胞介素-1β的蛋白表达水平。
von Frey 纤维试验结果表明，G-CSF 显著减轻 CCI 模型引起的机械性痛觉过敏。免疫组织化学显示，与载体组大鼠相比，G-CSF 减少了同侧背角中 p-p38MAPK 阳性细胞的数量。免疫荧光双重染色显示，脊髓背角中表达 p-p38MAPK 的细胞主要是小胶质细胞。Western blot 分析表明，与载体组大鼠相比，G-CSF 降低了同侧背角中 p-p38MAPK 和白细胞介素-1β的表达水平。
本研究结果表明，延迟 G-CSF 治疗在外周神经损伤性疼痛动物模型中具有有益作用。
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