Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia.
Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia.
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DOI：
10.1016/j.bbi.2016.03.003
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Shubayev VI
中科院分区：
文献类型：
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作者：
Ko JS;Eddinger KA;Angert M;Chernov AV;Dolkas J;Strongin AY;Yaksh TL;Shubayev VI
机械感觉纤维被髓磷脂包裹，髓磷脂是一种独特的多层膜，允许有益的神经传导。髓鞘损伤被认为是造成由无害的触觉刺激（即机械异常性疼痛）引起的严重疼痛的原因。我们的早期（Liu et al .， J. Neuroinflammation, 9(1): 119, 2012）和目前的数据表明，在完整的坐骨神经中单次注射髓鞘碱性蛋白衍生肽（MBP84-104）可在雌性大鼠中产生持久的（约30天）机械异常性疼痛。MBP84-104肽代表免疫优势表位，需要T细胞维持异常性疼痛。令人惊讶的是，只有全身加巴喷丁（电压门控制钙通道α2δ1的配体），而酮妥拉酸（COX抑制剂）、利多卡因（钠通道阻滞剂）或MK801 （NMDA拮抗剂）不能逆转腹膜内MBP84-104诱导的异位性痛。坐骨神经全基因组转录谱分析和表达变化的生物信息学分析发现，白细胞介素(IL)-6是MBP84-104在对照和胸腺T细胞缺陷裸鼠中诱导的主要细胞因子。腹膜内注射MBP84-104导致单侧异常性疼痛和单侧脊髓节段（神经元和星形胶质细胞）IL-6增加。功能阻断IL-6抗体的鞘内递送部分通过DRG大直径初级传入神经的转录作用减少了异位性疼痛。我们的数据表明，MBP调节神经系统中IL-6的表达，脊髓IL-6活性介导由体感觉神经系统损伤或疾病后释放的MBP表位刺激的伤害性加工。
Mechanosensory fibers are enveloped by myelin, a unique multilamellar membrane permitting salutatory neuronal conduction. Damage to myelin is thought to contribute to severe pain evoked by innocuous tactile stimulation (i.e. mechanical allodynia). Our earlier (Liu et al, J. Neuroinflammation, 9 (1): 119, 2012) and present data demonstrate that a single injection of a myelin basic protein-derived peptide (MBP84–104) into an intact sciatic nerve produces a robust and long-lasting (>30 days) mechanical allodynia in female rats. The MBP84-104 peptide represents the immunodominant epitope and requires T cells to maintain allodynia. Surprisingly, only systemic gabapentin (a ligand of voltage-gated calcium channel α2δ1), but not ketorolac (COX inhibitor), lidocaine (sodium channel blocker) or MK801 (NMDA antagonist) reverse allodynia induced by the intrasciatic MBP84-104. The genome-wide transcriptional profiling of the sciatic nerve followed by the bioinformatics analyses of the expression changes identified interleukin (IL)-6 as the major cytokine induced by MBP84-104 in both the control and athymic T cell-deficient nude rats. The intrasciatic MBP84-104 injection resulted in both unilateral allodynia and unilateral IL-6 increase the segmental spinal cord (neurons and astrocytes). An intrathecal delivery of a function-blocking IL-6 antibody reduced the allodynia in part by the transcriptional effects in large-diameter primary afferents in DRG. Our data suggest that MBP regulates IL-6 expression in the nervous system and that the spinal IL-6 activity mediates nociceptive processing stimulated by the MBP epitopes released after damage or disease of the somatosensory nervous system.