Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research, National Study Center for Trauma and EMS, University of Maryland, School of Medicine, Bressler Research Building, 655 W. Baltimore Street, Room #6-009, Baltimore, MD 21201, USA.
Neurotherapeutics. 2013 Jul;10(3):520-38. doi: 10.1007/s13311-013-0198-1.
Spinal cord injury (SCI) causes not only sensorimotor and cognitive deficits, but frequently also severe chronic pain that is difficult to treat (SCI pain). We previously showed that hyperesthesia, as well as spontaneous pain induced by electrolytic lesions in the rat spinothalamic tract, is associated with increased spontaneous and sensory-evoked activity in the posterior thalamic nucleus (PO). We have also demonstrated that rodent impact SCI increases cell cycle activation (CCA) in the injury region and that post-traumatic treatment with cyclin dependent kinase inhibitors reduces lesion volume and motor dysfunction. Here we examined whether CCA contributes to neuronal hyperexcitability of PO and hyperpathia after rat contusion SCI, as well as to microglial and astroglial activation (gliopathy) that has been implicated in delayed SCI pain. Trauma caused enhanced pain sensitivity, which developed weeks after injury and was correlated with increased PO neuronal activity. Increased CCA was found at the thoracic spinal lesion site, the lumbar dorsal horn, and the PO. Increased microglial activation and cysteine-cysteine chemokine ligand 21 expression was also observed in the PO after SCI. In vitro, neurons co-cultured with activated microglia showed up-regulation of cyclin D1 and cysteine-cysteine chemokine ligand 21 expression. In vivo, post-injury treatment with a selective cyclin dependent kinase inhibitor (CR8) significantly reduced cell cycle protein induction, microglial activation, and neuronal activity in the PO nucleus, as well as limiting chronic SCI-induced hyperpathia. These results suggest a mechanistic role for CCA in the development of SCI pain, through effects mediated in part by the PO nucleus. Moreover, cell cycle modulation may provide an effective therapeutic strategy to improve reduce both hyperpathia and motor dysfunction after SCI.
脊髓损伤 (SCI) 不仅会导致感觉运动和认知功能障碍，还常常导致难以治疗的严重慢性疼痛 (SCI 疼痛)。我们之前的研究表明，在大鼠的脊髓丘脑束中进行电刺激损伤后，感觉过敏以及自发性疼痛与后丘脑核 (PO) 中自发性和感觉诱发活动的增加有关。我们还证明了啮齿动物的冲击性 SCI 会增加损伤区域的细胞周期激活 (CCA)，并且创伤后使用细胞周期蛋白依赖性激酶抑制剂治疗可减少损伤体积和运动功能障碍。在这里，我们研究了 CCA 是否会导致 PO 神经元过度兴奋和大鼠挫伤 SCI 后的痛觉过敏，以及微胶质细胞和星形胶质细胞的激活 (神经胶质病)，后者与延迟性 SCI 疼痛有关。创伤导致疼痛敏感性增强，这种疼痛在受伤后数周发展，并与 PO 神经元活性增加相关。在胸段脊髓损伤部位、腰背部角和 PO 中发现 CCA 增加。SCI 后 PO 中还观察到小胶质细胞激活和半胱氨酸-半胱氨酸趋化因子配体 21 表达增加。在体外，与激活的小胶质细胞共培养的神经元表现出 cyclin D1 和半胱氨酸-半胱氨酸趋化因子配体 21 表达的上调。在体内，损伤后用选择性细胞周期蛋白依赖性激酶抑制剂 (CR8) 治疗可显著减少 PO 核中细胞周期蛋白诱导、小胶质细胞激活和神经元活性，从而限制慢性 SCI 诱导的痛觉过敏。这些结果表明 CCA 在 SCI 疼痛的发展中具有机制作用，部分通过 PO 核介导。此外，细胞周期调节可能为改善 SCI 后痛觉过敏和运动功能障碍提供有效的治疗策略。
