Winkelstein B A, Rutkowski M D, Sweitzer S M, Pahl J L, DeLeo J A
Department of Anesthesiology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
J Comp Neurol. 2001 Oct 15;439(2):127-39.
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-1beta, 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.
神经系统损伤转变为慢性疼痛状态的具体机制仍未明确。从历史上看，人们一直认为背根神经节（DRG）近端或远端的损伤会产生不同的病理变化，表现为不同严重程度的症状。本研究调查了相对于DRG的损伤部位在以下方面的作用：（1）引发行为反应；（2）诱导脊髓神经免疫激活；（3）对药物干预的反应。大鼠接受DRG远端的L5脊髓神经横断或DRG近端的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激活情况。在单独的研究中，通过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）和一种全身性免疫抑制剂（来氟米特）进行鞘内药物干预，以确定它们在这些损伤模型中的相对有效性。通过机械性异常性疼痛和热痛觉过敏评估的行为反应在两种持续性疼痛模型中几乎相同，这表明行为测试可能不是损伤的敏感指标。两种损伤中脊髓IL-1β、IL-6、IL-10和TNF mRNA以及IL-6蛋白均显著升高。两种损伤模型中表达的总体幅度和时间模式相似。两种损伤在L5脊髓中的小胶质细胞和星形胶质细胞激活程度也相似。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，这表明神经根损伤引发的中枢介导反应比周围神经损伤更强烈。总体而言，这些数据表明在这些解剖结构不同的损伤中存在不同的伤害性机制，而行为测试或本研究中使用的神经免疫标志物无法区分这些机制。
