Synergistic activation of ERK1/2 between A-fiber neurons and glial cells in the DRG contributes to pain hypersensitivity after tissue injury.
Synergistic activation of ERK1/2 between A-fiber neurons and glial cells in the DRG contributes to pain hypersensitivity after tissue injury.
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DOI：
10.1177/1744806918767508
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发表时间：
2018-01
期刊：
影响因子：
3.3
通讯作者：
Amaya F
中科院分区：
文献类型：
--
作者：
Yamakita S;Horii Y;Takemura H;Matsuoka Y;Yamashita A;Yamaguchi Y;Matsuda M;Sawa T;Amaya F
持续损伤产生的强烈伤害性信号激活初级传入伤害性系统，产生外周致敏。背根神经节ERK1/2磷酸化可用于观察有害刺激后的细胞内信号活动。本研究旨在探讨ERK1/2磷酸化对原代传入神经元组织损伤的时空特征。在Sprague-Dawley大鼠后爪做足底切口（n =150）。左布比卡因注射于足跖部和踝关节，MEK（丝裂原活化蛋白激酶）抑制剂注射于足跖部，卡贝诺洛酮腹腔注射间隙连接和潘联蛋白通道双抑制剂。行为学研究疼痛超敏反应，免疫组化和Western blot检测ERK1/2磷酸化在背根神经节和后爪的表达。切口后背根神经节ERK1/2磷酸化（基线时26.8±2.9%，2min时65.6±3.6%，2h时26.3±3.4%）。NF-200阳性的a纤维神经元和卫星胶质细胞磷酸化ERK1/2阳性。MEK抑制剂可消除损伤性疼痛超敏反应。左布比卡因抑制ERK1/2磷酸化诱导，卡贝诺洛酮在损伤后2 min抑制神经胶质磷酸化ERK1/2，卡贝诺洛酮在损伤后1 h抑制疼痛超敏反应和神经元磷酸化ERK1/2。损伤后a纤维神经元和卫星神经胶质细胞ERK1/2的磷酸化有助于疼痛超敏反应的产生。神经元与卫星胶质细胞之间的信号交流延长了组织损伤后1小时神经元ERK1/2磷酸化和疼痛超敏反应的持续时间。
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. 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. 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. 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.
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