Journal
NEUROPHARMACOLOGY
Volume 165, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2019.107816
Keywords
Cntnap2; Akt-mTOR signaling pathway; Dorsal root ganglion; Pain
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Funding
- National Natural Science Foundation of China [81728013, 81671101]
- Education Department Foundation of Hunan Province [19A354]
- Natural Science Foundation of Hunan Province [2019JJ40204]
- Key Research and Development Programs from Hunan Province [2018DK2010, 2018DK2013]
- Fundamental Research Funds for the Central Universities of Central South University [2018zzts398]
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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 Cnmap2(-/-) 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.
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