Contactin-associated protein-like 2 (CNTNAP2 or CASPR2) is a neuronal transmembrane protein of the neurexin superfamily that is involved in many neurological diseases, such as autism and pain hypersensitivity. We recently found that Cntnap2-/- mice showed elevated Akt-mTOR activity in the brain, and suppression of the Akt-mTOR pathway rescued the social deficit in Cntnap2-/- mice. In this study, we found that the dorsal root ganglion (DRG) from Cntnap2-/- mice also showed hyperactive Akt-mTOR signaling. Treatment with the Akt inhibitor LY94002 or the mTOR inhibitor rapamycin attenuated pain-related hypersensitivity to noxious mechanical stimuli, heat, and inflammatory substances. Further, suppression of mTOR signaling by rapamycin decreased DRG neuronal hyperexcitability. We further indicated that treatment with the FDA-approved drug metformin normalized the hyperactive Akt-mTOR signaling, and attenuated pain-related hypersensitivity in Cntnap2-/- mice. Our results thus identified hyperactive Akt-mTOR signaling pathway as a promising therapeutic target for pain-related hypersensitivity in patients with dysfunction of CNTNAP2.

中文翻译：

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过度活跃的Akt-mTOR通路可作为Cntnap2缺陷小鼠疼痛超敏反应的治疗靶标。

接触蛋白相关蛋白样2（CNTNAP2或CASPR2）是神经毒素超家族的神经元跨膜蛋白，与许多神经系统疾病有关，例如自闭症和疼痛超敏反应。我们最近发现，Cntnap2-/-小鼠在大脑中显示出升高的Akt-mTOR活性，并且抑制Akt-mTOR途径可以挽救Cntnap2-/-小鼠的社交缺陷。在这项研究中，我们发现来自Cntnap2-/-小鼠的背根神经节（DRG）也显示过活跃的Akt-mTOR信号传导。用Akt抑制剂LY94002或mTOR抑制剂雷帕霉素治疗可减轻与疼痛有关的对有害机械刺激，热和炎性物质的超敏反应。此外，雷帕霉素对mTOR信号的抑制作用降低了DRG神经元的过度兴奋性。我们进一步表明，用FDA批准的药物二甲双胍治疗可使Ant-mTOR信号亢进正常化，并减轻Cntnap2-/-小鼠疼痛相关的超敏反应。因此，我们的结果确定了过度活跃的Akt-mTOR信号通路是CNTNAP2功能障碍患者疼痛相关超敏反应的有希望的治疗靶标。