Downregulation of GIRK2 Mediated by PPARγ Inhibition in DRG Contributes to the Neuropathic Pain Induced by Spare Nerve Injury

Abstract

Neuropathic pain, as the most common chronic and intractable neurological disorder, seriously endangers the health and even life of patients. Due to the unclear mechanism, there is no effective treatment for neuropathic pain at present. Here, we used spared nerve injury (SNI) rat model to investigate the underlying mechanism involved in neuropathic pain. We found that SNI significantly decreased the expression of G protein-coupled inwardly rectifying potassium channel subunit 2 (GIRK2) and peroxisome proliferation-activated receptor gamma (PPARγ) in dorsal root ganglion (DRG). Activation of GIRK2 by intrathecal injection of activators-ML-297 or overexpression of GIRK2 by intrathecal injection of adenovirus associated virus (AAVs)-AAV-GIRK2-EGFP remarkably attenuated the mechanical allodynia induced by SNI in rats. Similarly, activation or overexpression of PPARγ also relieved the SNI-induced mechanical allodynia. We further found that the expression of PPARγ was co-localized with GIRK2-positive neurons, and overexpression of PPARγ rescued the down-regulation of GIRK2 induced by SNI. The results of chromatin immunoprecipitation (ChIP) assays further showed that PPARγ was bound to the potential binding site in the promoter region of GIRK2, and overexpression of PPARγ recovered the binding in GIRK2 promoter region in DRG, which was decreased by SNI. Altogether, our results suggested that the reduction of PPARγ induced downregulation of GIRK2 in DRG, whichwas involved in SNI-induced mechanical allodynia.