Sweitzer S, Martin D, DeLeo J A
Department of Pharmacology and Toxicology, Hinman Box 7650, Dartmouth College, Hanover, NH 03755, USA.
Neuroscience. 2001;103(2):529-39. doi: 10.1016/s0306-4522(00)00574-1.
The expression of interleukin-1beta and tumor necrosis factor has previously been shown to be up-regulated in the spinal cord of several rat mononeuropathy models. This present study was undertaken to determine whether blocking the action of central interleukin-1beta and tumor necrosis factor attenuates mechanical allodynia in a gender-specific manner in a rodent L5 spinal nerve transection model of neuropathic pain, and whether this inhibition occurs via down-regulation of the central cytokine cascade or blockade of glial activation. Interleukin-1 receptor antagonist or soluble tumor necrosis factor receptor was administered intrathecally via lumbar puncture to male Holtzman rats in a preventative pain strategy, in which therapy was initiated 1h prior to surgery. Administration of soluble tumor necrosis factor receptor attenuated mechanical allodynia, while interleukin-1 receptor antagonist alone was unable to decrease allodynia. Interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor, administered to both male and female rats in a preventative pain strategy, significantly reduced mechanical allodynia in a dose-dependent manner (P<0.01). The magnitude of attenuation in allodynia was similar in both males and females. Immunohistochemistry on L5 spinal cord revealed similar astrocytic and microglial activation regardless of treatment. At days 3 and 7 post-transection, animals receiving daily interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibited significantly less interleukin-6, but not interleukin-1beta, in the L5 spinal cord compared to vehicle-treated animals. In an existing pain paradigm, in which treatment was initiated on day 7 post-transection, interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor attenuated mechanical allodynia (P<0.05) in male rats. These findings further support a role for central interleukin-1beta and tumor necrosis factor in the development and maintenance of neuropathic pain through induction of a proinflammatory cytokine cascade.
先前的研究表明，在几种大鼠单神经病变模型的脊髓中，白细胞介素-1β和肿瘤坏死因子的表达上调。本研究旨在确定在啮齿动物L5脊髓神经横断性神经病理性疼痛模型中，阻断中枢白细胞介素-1β和肿瘤坏死因子的作用是否以性别特异性方式减轻机械性异常性疼痛，以及这种抑制是否通过下调中枢细胞因子级联反应或阻断胶质细胞激活而发生。采用预防性疼痛策略，通过腰椎穿刺向雄性霍尔兹曼大鼠鞘内注射白细胞介素-1受体拮抗剂或可溶性肿瘤坏死因子受体，治疗在手术前1小时开始。可溶性肿瘤坏死因子受体的给药减轻了机械性异常性疼痛，而单独使用白细胞介素-1受体拮抗剂则无法减轻异常性疼痛。在预防性疼痛策略中，将白细胞介素-1受体拮抗剂与可溶性肿瘤坏死因子受体联合应用于雄性和雌性大鼠，均以剂量依赖性方式显著减轻了机械性异常性疼痛（P<0.01）。雄性和雌性大鼠异常性疼痛减轻的程度相似。L5脊髓的免疫组织化学显示，无论治疗如何，星形胶质细胞和小胶质细胞的激活情况相似。在横断后第3天和第7天，与接受载体治疗的动物相比，每天接受白细胞介素-1受体拮抗剂与可溶性肿瘤坏死因子受体联合治疗的动物，其L5脊髓中的白细胞介素-6显著减少，但白细胞介素-1β没有减少。在现有的疼痛模型中，治疗在横断后第7天开始，白细胞介素-1受体拮抗剂与可溶性肿瘤坏死因子受体联合应用减轻了雄性大鼠的机械性异常性疼痛（P<0.05）。这些发现进一步支持了中枢白细胞介素-1β和肿瘤坏死因子通过诱导促炎细胞因子级联反应在神经病理性疼痛的发生和维持中发挥作用。
