Reactive Oxygen Species Derived from NOX1/NADPH Oxidase Enhance Inflammatory Pain

• DOI: 10.1523/jneurosci.1857-08.2008
• Publication Date: 2008-09-17T16:24:35Z
• Authors: Masakazu Ibi; Kuniharu Matsuno; Dai Shiba; Masato Katsuyama; Kazumi Iwata; Tomoko Kakehi; Takayuki Nakagawa; Kazunori Sango; Yasuhito Shirai; Takahiko Yokoyama; Shuji Kaneko; Naoaki Saito; Chihiro Yabe-Nish...
• Keywords: Inflammation; Mice, Knockout; 0301 basic medicine; 0303 health sciences; Nociceptors; Pain; TRPV Cation Channels; Free Radical Scavengers; Protein Kinase C-epsilon; Mice; Oxidative Stress; Protein Transport; 03 medical and health sciences; Hyperalgesia; Ganglia, Spinal; NADPH Oxidase 1; Animals; NADH, NADPH Oxidoreductases; Calcium Signaling; Neurons, Afferent; Inflammation Mediators; Reactive Oxygen Species; Cells, Cultured

The involvement of reactive oxygen species (ROS) in an augmented sensitivity to painful stimuli (hyperalgesia) during inflammation has been suggested, yet how and where ROS affect the pain signaling remain unknown. Here we report a novel role for the superoxide-generating NADPH oxidase in the development of hyperalgesia. In mice lackingNox1(Nox1−/Y), a catalytic subunit of NADPH oxidase, thermal and mechanical hyperalgesia was significantly attenuated, whereas no change in nociceptive responses to heat or mechanical stimuli was observed. In dorsal root ganglia (DRG) neurons ofNox1+/Y, pretreatment with chemical mediators bradykinin, serotonin, or phorbol 12-myristate 13-acetate (PMA) augmented the capsaicin-induced calcium increase, whereas this increase was significantly attenuated in DRG neurons ofNox1−/Y. Concomitantly, PMA-induced translocation of PKCε was markedly perturbed inNox1−/YorNox1+/YDRG neurons treated with ROS-scavenging agents. In cells transfected with tagged PKCε, hydrogen peroxide induced translocation and a reduction in free sulfhydryls of full-length PKCε but not of the deletion mutant lacking the C1A domain. These findings indicate that NOX1/NADPH oxidase accelerates the translocation of PKCε in DRG neurons, thereby enhancing the TRPV1 activity and the sensitivity to painful stimuli.