Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan, ROC Transgenic & Molecular Immunogenetics Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan, ROC Graduate Institutes of Clinical Medical Sciences, Chang Gung University, Linkou, Taiwan, ROC Department of Anesthesiology, Taipei-Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC Department of Medicine, Chang Gung University, Linkou, Taiwan, ROC.
Pain. 2012 Jun;153(6):1283-1291. doi: 10.1016/j.pain.2012.03.008. Epub 2012 Apr 10.
Accumulated evidence suggests that the C-C motif chemokine ligand 5 (CCL5) modulates migration of inflammatory cells in several pathological conditions. This study tested the hypothesis that lack of CCL5 would modulate the recruitment of inflammatory cells to painful, inflamed sites and could attenuate pain in a murine chronic neuropathic pain model. Nociceptive sensitization, immune cell infiltration, multiple cytokine expression, and opioid peptide expression in damaged nerves were studied in wild-type (CCL5 +/+) and CCL5-deficient (CCL5 -/-) mice after partial sciatic nerve ligation (PSNL). Results indicated that CCL5 -/- mice had less behavioral hypersensitivity after PSNL. Macrophage infiltration and proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, and interferon-γ) in damaged nerves following PSNL were significantly decreased in CCL5 -/- mice. Conversely, several antiinflammatory cytokine (IL-4 and IL-10) proteins were significantly increased in CCL5 -/- animals and the expression of enkephalin, β-endorphin, and dynorphin mRNA was significantly lower than in wild-type control mice. These results represent the first evidence that CCL5 is capable of regulating the pathway that controls hyperalgesia at the level of the peripheral injured site in a murine chronic neuropathic pain model. We demonstrated that lack of CCL5 modulated cell infiltration and the proinflammatory milieu within the injured nerve. Attenuated behavioral hypersensitivity in CCL5 -/- mice observed in the current study could be a result of decreased macrophage infiltration, mobilization, and functional ability at injured sites. Collectively, the present study results suggest that CCL5 receptor antagonists may ultimately provide a novel class of analgesics for therapeutic intervention in chronic neuropathic pain.
积累的证据表明，C-C 基序趋化因子配体 5（CCL5）调节几种病理条件下炎症细胞的迁移。本研究检验了以下假设：缺乏 CCL5 会调节炎症细胞向疼痛、发炎部位的募集，并可能减轻慢性神经病理性疼痛模型中小鼠的疼痛。在坐骨神经部分结扎（PSNL）后，研究了野生型（CCL5+/+）和 CCL5 缺陷型（CCL5-/-）小鼠的伤害感受敏化、免疫细胞浸润、多种细胞因子表达和损伤神经中的阿片肽表达。结果表明，CCL5-/-小鼠在 PSNL 后行为敏感性较低。PSNL 后损伤神经中的巨噬细胞浸润和促炎细胞因子（肿瘤坏死因子-α、白细胞介素[IL]-1β、IL-6 和干扰素-γ）在 CCL5-/-小鼠中明显减少。相反，几种抗炎细胞因子（IL-4 和 IL-10）蛋白在 CCL5-/-动物中明显增加，而内啡肽、β-内啡肽和强啡肽 mRNA 的表达明显低于野生型对照小鼠。这些结果代表了第一个证据，表明 CCL5 能够调节慢性神经病理性疼痛模型中损伤部位周围控制痛觉过敏的途径。我们证明了 CCL5 的缺乏调节了损伤神经内的细胞浸润和促炎环境。在当前研究中观察到的 CCL5-/-小鼠行为敏感性降低可能是由于损伤部位巨噬细胞浸润、动员和功能能力降低所致。总之，本研究结果表明，CCL5 受体拮抗剂最终可能为慢性神经病理性疼痛的治疗干预提供一类新型的镇痛药。
