Ko Justin S, Eddinger Kelly A, Angert Mila, Chernov Andrei V, Dolkas Jennifer, Strongin Alex Y, Yaksh Tony L, Shubayev Veronica I
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea.
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA.
Brain Behav Immun. 2016 Aug;56:378-89. doi: 10.1016/j.bbi.2016.03.003. Epub 2016 Mar 9.
Mechanosensory fibers are enveloped by myelin, a unique multilamellar membrane permitting saltatory 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., 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 (>30days) 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.
机械感觉纤维被髓鞘包裹，髓鞘是一种独特的多层膜，可允许神经元进行跳跃式传导。髓鞘损伤被认为会导致无害触觉刺激引发的剧痛（即机械性异常性疼痛）。我们早期（Liu等人，2012年）以及目前的数据表明，向完整的坐骨神经中单次注射髓鞘碱性蛋白衍生肽（MBP84-104）会在雌性大鼠中产生强烈且持久（>30天）的机械性异常性疼痛。MBP84-104肽代表免疫显性表位，且需要T细胞来维持异常性疼痛。令人惊讶的是，只有全身性加巴喷丁（电压门控钙通道α2δ1的配体）能逆转坐骨神经内注射MBP84-104所诱导的异常性疼痛，而酮咯酸（COX抑制剂）、利多卡因（钠通道阻滞剂）或MK801（NMDA拮抗剂）则不能。对坐骨神经进行全基因组转录谱分析，随后对表达变化进行生物信息学分析，结果确定白细胞介素（IL）-6是MBP84-104在对照和无胸腺T细胞缺陷裸鼠中诱导产生的主要细胞因子。坐骨神经内注射MBP84-104导致单侧异常性疼痛以及单侧IL-6在节段性脊髓（神经元和星形胶质细胞）中增加。鞘内注射功能阻断性IL-6抗体部分减轻了异常性疼痛，这是通过对背根神经节中大直径初级传入神经的转录作用实现的。我们的数据表明，MBP调节神经系统中IL-6的表达，并且脊髓IL-6活性介导了由躯体感觉神经系统损伤或疾病后释放的MBP表位刺激引起的伤害性处理过程。
