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TBI-induced nociceptive sensitization is regulated by histone acetylation

机译：TBI引起的伤害感受敏化受组蛋白乙酰化调节

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Chronic pain after traumatic brain injury (TBI) is very common, but the mechanisms linking TBI to pain and the pain-related interactions of TBI with peripheral injuries are poorly understood. In these studies we pursued the hypothesis that TBI pain sensitization is associated with histone acetylation in the rat lateral fluid percussion model. Some animals received hindpaw incisions in addition to TBI to mimic polytrauma. Neuropathological analysis of brain tissue from sham and TBI animals revealed evidence of bleeding, breakdown of the blood brain barrier, in the cortex, hippocampus, thalamus and other structures related to pain signal processing. Mechanical allodynia was measured in these animals for up to eight weeks post-injury. Inhibitors of histone acetyltransferase (HAT) and histone deacetylase (HDAC) were used to probe the role of histone acetylation in such pain processing. We followed serum markers including glial fibrillary acidic protein (GFAP), neuron-specific enolase 2 (NSE) myelin basic protein (MBP) and S100β to gauge TBI injury severity. Our results showed that TBI caused mechanical allodynia in the hindpaws of the rats lasting several weeks. Hindpaws contralateral to TBI showed more rapid and profound sensitization than ipsilateral hindpaws. The inhibition of HAT using curcumin 50?mg/kg s.c reduced mechanical sensitization while the HDAC inhibitor suberoylanilide hydroxamic acid 50?mg/kg i.p. prolonged sensitization in the TBI rats. Immunohistochemical analyses of spinal cord tissue localized changes in the level of acetylation of the H3K9 histone mark to dorsal horn neurons. Taken together, these findings demonstrate that TBI induces sustained nociceptive sensitization, and changes in spinal neuronal histone proteins may play an important role. Highlights ? Pain after traumatic brain injury (TBI) is common and often persistent. ? Using the rat lateral fluid percussion model, it was observed that hindpaw allodynia is present for three weeks after TBI. ? Damage to pain processing areas of the brain can be demonstrated after TBI. ? Agents regulating the epigenetic acetylation of histone proteins modified the time course of TBI-induced allodynia.
机译：创伤性脑损伤（TBI）后的慢性疼痛非常普遍，但人们对TBI与疼痛之间的联系以及TBI与周围性损伤的疼痛相关相互作用的了解却很少。在这些研究中，我们进行了以下假设，即在大鼠侧向流体打击模型中，TBI疼痛敏化与组蛋白乙酰化有关。除TBI外，一些动物还接受了后爪切口以模仿多发伤。对假手术和TBI动物的脑组织进行神经病理学分析，发现皮质，海马，丘脑和其他与疼痛信号处理相关的出血，血脑屏障破裂的证据。在这些动物受伤后长达八周的时间内测量其机械性异常性疼痛。组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰基酶（HDAC）的抑制剂被用来探究组蛋白乙酰化在此类疼痛过程中的作用。我们跟踪了血清标志物，包括神经胶质纤维酸性蛋白（GFAP），神经元特异性烯醇化酶2（NSE）髓鞘碱性蛋白（MBP）和S100β，以评估TBI损伤的严重程度。我们的结果表明，TBI引起大鼠后足的机械性异常性疼痛持续数周。与TBI对侧的后足比同侧的后足表现出更快，更深刻的敏化作用。姜黄素50？mg / kg s.c对HAT的抑制作用降低了机械致敏性，而HDAC抑制剂辛二酰苯胺异羟肟酸50？mg / kg腹腔注射对HAT的抑制作用降低了。延长了TBI大鼠的致敏性。脊髓组织的免疫组织化学分析将H3K9组蛋白标记的乙酰化水平局部化为背角神经元。综上所述，这些发现表明TBI诱导持续的伤害性敏化，并且脊髓神经元组蛋白的变化可能起重要作用。强调 ？创伤性脑损伤（TBI）后的疼痛很常见，而且经常持续存在。 ？使用大鼠侧面液体撞击模型，观察到TBI后三周出现后足异常性疼痛。 ？ TBI后可证明对大脑疼痛处理区域的损害。 ？调节组蛋白的表观遗传学乙酰化作用的试剂改变了TBI诱导的异常性疼痛的时程。

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