1 Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
2 Research Unit for the Neurobiology of Pain, Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Mol Pain. 2018 Jan-Dec;14:1744806918767508. doi: 10.1177/1744806918767508.
Background Intense nociceptive signaling arising from ongoing injury activates primary afferent nociceptive systems to generate peripheral sensitization. ERK1/2 phosphorylation in dorsal root ganglion can be used to visualize intracellular signal activity immediately after noxious stimulation. The aim of this study was to investigate spatiotemporal characteristics of ERK1/2 phosphorylation against tissue injury in the primary afferent neurons. Methods Plantar incisions were made in the hind paws of Sprague-Dawley rats (n =150). Levobupivacaine was injected into the plantar aspect of the paws and ankles, Mitogen-activated protein kinase kinase (MEK) inhibitor was injected into the paw, and carbenoxolone, dual inhibitor of the gap junction and pannexin channel, was intraperitoneally injected. Pain hypersensitivity was investigated by a behavioral study, while phosphorylated ERK1/2 was detected in dorsal root ganglion and hind paw using immunohistochemistry and Western blot. Results Phosphorylated ERK1/2 was induced in dorsal root ganglion (26.8 ± 2.9% at baseline, 65.6 ± 3.6% at 2 min, and 26.3 ± 3.4% at 2 h) after the incision. NF-200 positive A-fiber neurons and satellite glial cells were positive for phosphorylated ERK1/2. Injury-induced pain hypersensitivity was abolished by MEK inhibitor. Levobupivacaine treatment inhibited phosphorylated ERK1/2 induction, carbenoxolone treatment inhibited glial phosphorylated ERK1/2 at 2 min after the injury, and carbenoxolone inhibited pain hypersensitivity and neuronal phosphorylated ERK1/2 at 1 h after the injury. Conclusion ERK1/2 phosphorylation in A-fiber neurons and satellite glial cells immediately after injury contributes to the generation of pain hypersensitivity. Signal communication between neurons and satellite glial cells expands the duration of neuronal ERK1/2 phosphorylation and pain hypersensitivity at 1 h after tissue injury.
持续的伤害性刺激引起的强烈伤害性信号激活初级传入伤害性系统，产生外周敏化。背根神经节中 ERK1/2 的磷酸化可用于在有害刺激后立即观察细胞内信号活性。本研究旨在探讨初级传入神经元组织损伤后 ERK1/2 磷酸化的时空特征。
在 Sprague-Dawley 大鼠的后爪足底做切口（n=150）。将左布比卡因注入足底和踝关节，将丝裂原活化蛋白激酶激酶（MEK）抑制剂注入爪，将缝隙连接和连接蛋白通道的双重抑制剂 carbenoxolone 注入腹腔。通过行为研究来研究痛觉过敏，同时通过免疫组织化学和 Western blot 检测背根神经节和后爪中磷酸化 ERK1/2。
切口后，背根神经节中诱导磷酸化 ERK1/2（基础水平 26.8±2.9%，2 分钟时 65.6±3.6%，2 小时时 26.3±3.4%）。NF-200 阳性 A 纤维神经元和卫星神经胶质细胞磷酸化 ERK1/2 阳性。MEK 抑制剂可消除损伤诱导的痛觉过敏。左布比卡因处理抑制磷酸化 ERK1/2 的诱导，carbenoxolone 处理抑制损伤后 2 分钟时的神经胶质磷酸化 ERK1/2，carbenoxolone 抑制损伤后 1 小时时的痛觉过敏和神经元磷酸化 ERK1/2。
损伤后 A 纤维神经元和卫星神经胶质细胞中 ERK1/2 的磷酸化有助于痛觉过敏的产生。神经元和卫星神经胶质细胞之间的信号通讯扩大了组织损伤后 1 小时神经元 ERK1/2 磷酸化和痛觉过敏的持续时间。
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