Adenosine Monophosphate-activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain.
Adenosine Monophosphate-activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain.
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DOI：
10.1097/aln.0000000000000619
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发表时间：
2015-06
期刊：
影响因子：
8.8
通讯作者：
Weng HR
中科院分区：
文献类型：
--
作者：
Maixner DW;Yan X;Gao M;Yadav R;Weng HR
脊髓背角（SDH）中的神经炎症和功能失调的胶质谷氨酸转运体（GT）与神经病理性疼痛的发生有关。我们确定是否腺苷一磷酸活化蛋白激酶（AMPK）在SDH调节这些过程中的啮齿动物神经性疼痛。后爪对辐射热和机械刺激的回缩反应用于评估伤害性行为。通过Western印迹法测定与神经炎症和胶质细胞GT相关的脊髓标记物。AMPK活性通过基因和生物学手段进行调控。通过测量胶质GT的蛋白质表达和活性来确定胶质GT的调节。神经损伤引起的热痛敏大鼠（n = 5）SDH中AMPK活性降低，同时伴有星形胶质细胞活化，白细胞介素1 β（IL-1 β）产生增加，糖原合成酶激酶3β（GCK 3β）活性升高，胶质细胞谷氨酸转运体1（GLT 1）蛋白表达降低。在神经病大鼠（n = 10）中通过脊髓激活AMPK来逆转热痛觉过敏，并且在幼稚大鼠（n = 7至8）中通过抑制脊髓AMPK来诱导热痛觉过敏。脊髓AMPKα敲低（n = 6）和AMPKα1条件性敲低（n = 6）诱导热痛觉过敏和机械异常性疼痛。这些遗传改变模拟了神经损伤引起的分子标记物的变化。AMPK的药理学激活增强了神经病理性疼痛小鼠（n = 8）的胶质GT活性，并减弱了白细胞介素-1 β诱导的胶质谷氨酸转运蛋白-1内化（n = 4）。这些结果表明，提高脊髓AMPK活性可能是治疗神经病理性疼痛的有效方法。
Neuroinflammation and dysfunctional glial glutamate transporters (GTs) in the spinal dorsal horn (SDH) are implicated in the genesis of neuropathic pain. We determined if adenosine monophosphate-activated protein kinase (AMPK) in the SDH regulates these processes in rodents with neuropathic pain. Hind paw withdrawal responses to radiant heat and mechanical stimuli were used to assess nociceptive behaviors. Spinal markers related to neuroinflammation and glial GTs were determined by Western blotting. AMPK activities were manipulated pharmacologically and genetically. Regulation of glial GTs was determined by measuring protein expression and activities of glial GTs. AMPK activities were reduced in the SDH of rats (n = 5) with thermal hyperalgesia induced by nerve injury, which were accompanied with the activation of astrocytes, increased production of interleukin-1beta and activities of glycogen synthase kinase 3β, and suppressed protein expression of glial glutamate transporter-1. Thermal hyperalgesia was reversed by spinal activation of AMPK in neuropathic rats (n = 10), and induced by inhibiting spinal AMPK in naïve rats (n = 7 to 8). Spinal AMPKα knockdown (n = 6) and AMPKα1 conditional knockout (n = 6) induced thermal hyperalgesia and mechanical allodynia. These genetic alterations mimicked the changes of molecular markers induced by nerve injury. Pharmacological activation of AMPK enhanced glial GT activity in mice with neuropathic pain (n = 8) and attenuated glial glutamate transporter-1 internalization induced by interleukin-1β (n = 4). These findings suggest enhancing spinal AMPK activities could be an effective approach for the treatment of neuropathic pain.