Involvement of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin/peroxisome proliferator-activated receptor γ pathway for induction and maintenance of neuropathic pain
Involvement of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin/peroxisome proliferator-activated receptor γ pathway for induction and maintenance of neuropathic pain
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DOI：
10.1016/j.bbrc.2018.03.139
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发表时间：
2018-05-05
影响因子：
3.1
通讯作者：
Tanabe, Tsutomu
中科院分区：
文献类型：
--
作者：
Kondo, Daisuke;Saegusa, Hironao;Tanabe, Tsutomu
周围神经损伤引起神经病理性疼痛，其特征是触觉异常性疼痛和热痛敏。N型电压依赖性钙通道（VDCC）在神经病理性疼痛的发生中起着关键作用，因为缺乏N型VDCC的成孔亚基Ca（v）2.2的小鼠表现出触觉异常性疼痛和热痛觉过敏的症状大大减少。我们对野生型和N型VDCC敲除（KO）脊髓和脊神经结扎（SNL）损伤后几个疼痛相关脑区的基因表达谱的研究揭示了编码磷脂酰肌醇-3激酶（P13 K）催化亚基的基因表达的改变。PI 3 K/Akt/哺乳动物雷帕霉素靶蛋白（P13 K/Akt/mTOR）信号传导被认为对癌症发展非常重要，并且靶向该途径中的分子的药物已经在肿瘤学试验中进行了测试。在本研究中，我们已经测试了在脊髓神经损伤的小鼠中该通路中的分子表达的变化是否与神经病理性疼痛有因果关系。我们的研究结果表明，脊神经损伤诱导激活的N型VDCC和以下的Ca 2+进入通过这个通道可能会改变基因编码的P13 K催化亚基（p110 α和p110 γ），Akt，维甲酸X受体α（RXR α）和RXR γ的表达。此外，发现该途径中的分子的阻断剂在脊髓和脊髓上水平均有效减少神经性疼痛。因此，PI 3 K/Akt/mTOR/过氧化物酶体增殖物激活受体γ（PPAR γ）通路的激活将是神经病理性疼痛的诱导和维持的标志。(C)2018爱思唯尔公司All rights reserved.
Peripheral nerve injury induces neuropathic pain, which is characterized by the tactile allodynia and thermal hyperalgesia. N-type voltage-dependent Ca2+ channel (VDCC) plays pivotal roles in the development of neuropathic pain, since mice lacking Ca(v)2.2, the pore-forming subunit of N-type VDCC, show greatly reduced symptoms of both tactile allodynia and thermal hyperalgesia. Our study on gene expression profiles of the wild-type and N-type VDCC knockout (KO) spinal cord and several pain-related brain regions after spinal nerve ligation (SNL) injury revealed altered expression of genes encoding catalytic subunits of phosphatidylinositol-3 kinase (P13K). PI3K/Akt/mammalian target of rapamycin (P13K/Akt/mTOR) signaling is considered to be very important for cancer development and drugs targeting the molecules in this pathway have been tested in oncology trials. In the present study, we have tested whether the changes in expression of molecules in this pathway in mice having spinal nerve injury are causally related to neuropathic pain. Our results suggest that spinal nerve injury induces activation of N-type VDCC and the following Ca2+ entry through this channel may change the expression of genes encoding P13K catalytic subunits (p110 alpha and p110 gamma), Akt, retinoid X receptor alpha (RXR alpha) and RXR gamma. Furthermore, the blockers of the molecules in this pathway are found to be effective in reducing neuropathic pain both at the spinal and at the supraspinal levels. Thus, the activation of PI3K/Akt/mTOR/peroxisome proliferator activated receptor gamma (PPAR gamma) pathway would be a hallmark of the induction and maintenance of neuropathic pain. (C) 2018 Elsevier Inc. All rights reserved.