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.