Hyperactive Akt-mTOR pathway as a therapeutic target for pain hypersensitivity in Cntnap2-deficient mice

  • Neuropharmacology. 2020 Mar 15;165:107816. doi: 10.1016/j.neuropharm.2019.107816.
Xiaoliang Xing  1 ,  Kunyang Wu  2 ,  Yufan Dong  2 ,  Yimei Zhou  3 ,  Jing Zhang  2 ,  Fang Jiang  2 ,  Wang-Ping Hu  4 ,  Jia-Da Li  5
Affiliations
  • 1. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, Hunan, PR China; Hunan University of Medicine, Huaihua, 418000, Hunan, PR China; Hunan Key Laboratory of Animal Models for Human Diseases, Changsham, 410078, Hunan, PR China; Hunan Key Laboratory of Medical Genetics, Changsha, 410078, Hunan, PR China.
  • 2. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, Hunan, PR China; Hunan Key Laboratory of Animal Models for Human Diseases, Changsham, 410078, Hunan, PR China; Hunan Key Laboratory of Medical Genetics, Changsha, 410078, Hunan, PR China.
  • 3. Research Center of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning, 437100, Hubei, PR China.
  • 4. Research Center of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning, 437100, Hubei, PR China. Electronic address: [email protected].
  • 5. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, Hunan, PR China; Hunan Key Laboratory of Animal Models for Human Diseases, Changsham, 410078, Hunan, PR China; Hunan Key Laboratory of Medical Genetics, Changsha, 410078, Hunan, PR China. Electronic address: [email protected].
PMID: 31874168 DOI: 10.1016/j.neuropharm.2019.107816
Abstract

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.

Keywords
Akt-mTOR signaling pathway; Cntnap2; Dorsal root ganglion; Pain.
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