Department of Pharmacology and Neurobiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Biochem Biophys Res Commun. 2018 May 5;499(2):253-259. doi: 10.1016/j.bbrc.2018.03.139. Epub 2018 Mar 22.
Peripheral nerve injury induces neuropathic pain, which is characterized by the tactile allodynia and thermal hyperalgesia. N-type voltage-dependent Ca channel (VDCC) plays pivotal roles in the development of neuropathic pain, since mice lacking Ca2.2, 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 (PI3K). PI3K/Akt/mammalian target of rapamycin (PI3K/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 Ca entry through this channel may change the expression of genes encoding PI3K catalytic subunits (p110α and p110γ), Akt, retinoid X receptor α (RXRα) and RXRγ. 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 (PPARγ) pathway would be a hallmark of the induction and maintenance of neuropathic pain.
周围神经损伤会引起神经性疼痛，其特征是触觉过敏和热痛觉过敏。N 型电压依赖性钙通道（VDCC）在神经性疼痛的发展中起着关键作用，因为缺乏 Ca2.2（N 型 VDCC 的孔形成亚基）的小鼠表现出触觉过敏和热痛觉过敏症状大大减轻。我们对野生型和 N 型 VDCC 敲除（KO）脊髓以及脊神经结扎（SNL）损伤后几种与疼痛相关的脑区的基因表达谱进行的研究表明，编码磷酸肌醇-3 激酶（PI3K）催化亚基的基因表达发生改变。PI3K/Akt/雷帕霉素靶蛋白（PI3K/Akt/mTOR）信号通路被认为对癌症的发展非常重要，针对该通路中分子的药物已在肿瘤学试验中进行了测试。在本研究中，我们测试了脊髓神经损伤小鼠中该通路中分子表达的变化是否与神经性疼痛有因果关系。我们的结果表明，脊髓神经损伤会诱导 N 型 VDCC 的激活，通过该通道的后续钙内流可能会改变编码 PI3K 催化亚基（p110α 和 p110γ）、Akt、视黄酸 X 受体 α（RXRα）和 RXRγ 的基因表达。此外，该通路中分子的抑制剂被发现可有效减轻脊髓和脊髓上水平的神经性疼痛。因此，PI3K/Akt/mTOR/过氧化物酶体增殖物激活受体γ（PPARγ）通路的激活可能是诱导和维持神经性疼痛的标志。
