Tumor Necrosis Factor-α Induces Mechanical Allodynia after Spinal Nerve Ligation by Activation of p38 MAPK in Primary Sensory Neurons
Tumor Necrosis Factor-α Induces Mechanical Allodynia after Spinal Nerve Ligation by Activation of p38 MAPK in Primary Sensory Neurons
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DOI：
10.1523/jneurosci.23-07-02517.2003
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发表时间：
2003-04
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影响因子：
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通讯作者：
M. Schäfers;C. Svensson;C. Sommer;L. Sorkin
中科院分区：
文献类型：
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作者：
M. Schäfers;C. Svensson;C. Sommer;L. Sorkin
肿瘤坏死因子-α（TNF）参与神经病理性疼痛的起始。在体外，TNF激活p38丝裂原活化激酶。因此，我们研究了在脊髓神经结扎（SNL）后，TNF是否在体内激活p38级联反应以触发疼痛行为。在SNL前2天开始用TNF拮抗剂依那西普（1 mg，i. p.，每三天一次）减轻机械性异常性疼痛。SNL后1或7天开始治疗无效。同样，鞘内输注p38抑制剂（SB 203580，4 mg/d）是有效的，只有当它开始之前，但不是7天后SNL。对于两种治疗，停止治疗均导致异常性疼痛增加。在使用蛋白质印迹和免疫组织化学的单独实验中，分析了SNL单独或SNL与依那西普联合预处理后同侧腰髓和L5和L 6 DRG的总p38和磷酸化p38。在DRG中，激活的p38在SNL后5小时短暂升高，并在SNL后1天恢复至基线。磷酸化p38定位于小的TNF阳性DRG神经元。在脊髓中，p38在SNL后5 h至3d被激活，并在5d内恢复到基线。在DRG中，依那西普预处理阻断了p38激活，但脊髓未阻断。这些数据表明SNL治疗后，脊髓和DRG中磷酸化p38水平短暂升高。在DRG中，p38激活被全身性TNF抑制阻断。p38激活和异常性疼痛的平行抑制可能代表临床相关的治疗窗口。这些数据表明，TNF和p38在诱导神经性疼痛中的顺序作用。
Tumor necrosis factor-α (TNF) is implicated in the initiation of neuropathic pain. In vitro, TNF activates p38 mitogen-activated kinase. Accordingly, we investigated whether TNF activates the p38 cascade in vivo to trigger pain behavior after spinal nerve ligation (SNL). Treatment starting 2 d before SNL with the TNF antagonist etanercept (1 mg, i.p., every third day) attenuated mechanical allodynia. Treatment starting 1 or 7 d after SNL was ineffective. Similarly, intrathecal infusion of a p38 inhibitor (SB203580, 4 mg/d) was effective only if it was started before but not 7 d after SNL. For both treatments, the cessation of therapy resulted in increased allodynia. In separate experiments using Western blots and immunohistochemistry, ipsilateral lumbar spinal cord and L5 and L6 DRG were analyzed for total and phosphorylated p38 after SNL alone or SNL combined with etanercept pretreatment. In DRG, activated p38 was transiently elevated 5 hr after SNL and returned to baseline by 1 d after SNL. Phosphorylated p38 was localized in small TNF-positive DRG neurons. In spinal cord, p38 was activated between 5 hr and 3 d after SNL and returned to baseline within 5 d. In DRG, but not spinal cord, etanercept pretreatment blocked p38 activation. These data indicate that after SNL treatment, phosphorylated p38 levels in spinal cord and DRG are transiently elevated. In DRG, p38 activation is blocked by systemic TNF inhibition. Parallel inhibition of p38 activation and allodynia may represent a clinically relevant therapeutic window. These data suggest a sequential role for TNF and p38 in the induction of neuropathic pain.