Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment
Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment
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DOI：
10.1002/cne.2000
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发表时间：
2001-10
影响因子：
2.5
通讯作者：
B. Winkelstein;M. Rutkowski;S. Sweitzer;Janice L. Pahl;J. Deleo
中科院分区：
文献类型：
--
作者：
B. Winkelstein;M. Rutkowski;S. Sweitzer;Janice L. Pahl;J. Deleo
神经系统损伤成为慢性疼痛状态的具体机制尚未确定。历史上，人们认为背根神经节（DRG）近端或远端的损伤会产生不同的病理，表现为不同的症状严重程度。本研究调查了相对于DRG的损伤部位在（1）引发行为反应，（2）诱导脊髓神经免疫激活和（3）对药物干预的反应中的作用。大鼠接受背根神经节远端L5脊神经横断或背根神经节近端L5神经根损伤。比较研究评估了损伤后的行为伤害性反应、脊髓细胞因子mRNA和蛋白表达以及胶质细胞活化。在单独的研究中，使用选择性细胞因子拮抗剂（白细胞介素-1 [IL-1]受体拮抗剂和可溶性肿瘤坏死因子[TNF]受体）和全面免疫抑制剂（来氟米特）进行鞘内药物干预，以确定其在这些损伤范例中的相对有效性。机械异常性疼痛和热痛觉过敏的行为反应评估几乎是相同的两个模型的持续性疼痛，这表明行为测试可能不是一个敏感的措施的伤害。脊髓IL-1β、IL-6、IL-10和TNF mRNA以及IL-6蛋白在两种损伤中均显著升高。在两种损伤模型中，表达的总体幅度和时间模式相似。两种损伤的L5脊髓中小胶质细胞和星形胶质细胞活化的程度也相似。相比之下，药物治疗在减轻周围神经损伤的机械性异常性疼痛方面比神经根损伤更有效，这表明神经根损伤比周围神经损伤引起更强大的中枢介导反应。总体而言，这些数据暗示了这些解剖学上不同的损伤中的替代伤害感受机制，这些损伤不能通过本研究中使用的行为测试或神经免疫标记物来区分。神经学比较杂志439：127-139，2001.© 2001 Wiley利斯公司
The specific mechanisms by which nervous system injury becomes a chronic pain state remain undetermined. Historically, it has been believed that injuries proximal or distal to the dorsal root ganglion (DRG) produce distinct pathologies that manifest in different severity of symptoms. This study investigated the role of injury site relative to the DRG in (1) eliciting behavioral responses, (2) inducing spinal neuroimmune activation, and (3) responding to pharmacologic interventions. Rats received either an L5 spinal nerve transection distal to the DRG or an L5 nerve root injury proximal to the DRG. Comparative studies assessed behavioral nociceptive responses, spinal cytokine mRNA and protein expression, and glial activation after injury. In separate studies, intrathecal pharmacologic interventions by using selective cytokine antagonists (interleukin‐1 [IL‐1] receptor antagonist and soluble tumor necrosis factor [TNF] receptor) and a global immunosuppressant (leflunomide) were performed to determine their relative effectiveness in these injury paradigms. Behavioral responses assessed by mechanical allodynia and thermal hyperalgesia were almost identical in the two models of persistent pain, suggesting that behavioral testing may not be a sensitive measure of injury. Spinal IL‐1β, IL‐6, IL‐10, and TNF mRNA and IL‐6 protein were significantly elevated in both injuries. The overall magnitude of expression and temporal patterns were similar in both models of injury. The degree of microglial and astrocytic activation in the L5 spinal cord was also similar for both injuries. In contrast, the pharmacologic treatments were more effective in alleviating mechanical allodynia for peripheral nerve injury than nerve root injury, suggesting that nerve root injury elicits a more robust, centrally mediated response than peripheral nerve injury. Overall, these data implicate alternate nociceptive mechanisms in these anatomically different injuries that are not distinguished by behavioral testing or the neuroimmune markers used in this study. J. Comp. Neurol. 439:127–139, 2001. © 2001 Wiley‐Liss, Inc.