Role of the P2X7-Nrf2 Pathway in Hyperalgesia Induced by Chronic Compression of the Dorsal Root Ganglion

The aim of the present study was to test the hypothesis that purinergic P2X7 receptor (P2X7) is involved in neuropathic pain by influencing the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. The chronic compression of the dorsal root ganglion (DRG) model (hereafter termed CCD) was used to investigate the hypothesis. We analyzed the effect of P2X7 on Nrf2 activation and the expression of downstream molecules, heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1), in the DRG following CCD. We further assessed the role of extracellular signal-regulated kinases 5 (ERK5) in the development of hyperalgesia mediated by P2X7-Nrf2 pathway in CCD. In this study, phosphorylated Nrf2 (pNrf2) expression in CCD male rats was upregulated by treatment with the P2X7 agonist BzATP but reduced by administration of the P2X7 antagonist A438079. Furthermore, BzATP-induced pNrf2 upregulation was suppressed by ERK5 blockade using the antagonist BIX02189. Expression changes in HO-1 and NQO1 mirrored those of pNrf2. These results indicated that P2X7 participated in neuropathic pain that was associated with the activation of the ERK5-Nrf2 pathway in rats.