Critical role of ROS in capsaicin-induced hyperalgesia

Recent studies indicate that reactive oxygen species (ROS) are critically involved in persistent pain primarily through spinal mechanisms, thus suggesting ROS involvement in central sensitization. To investigate ROS involvement in central sensitization, the effects of ROS scavengers and donors on pain behaviors were examined in mice. The capsaicin-induced hyperalgesia was used as a pain model since it has 2 distinctive pain components, primary and secondary hyperalgesia representing peripheral and central sensitization, respectively. Foot withdrawal frequencies in response to von Frey filament stimuli were measured and used as an indicator of mechanical hyperalgesia. The production of mitochondrial ROS was examined by using a ROS sensitive dye MitoSox-Red. Mice developed primary and secondary mechanical hyperalgesia after capsaicin injection. A systemic or intrathecal ROS scavenger treatment significantly reduced secondary hyperalgesia, but not primary hyperalgesia, in a dose dependent manner. MitoSox positive dorsal horn neuron numbers were increased significantly after capsaicin treatment. This study suggests that ROS mediates the development and maintenance of capsaicin-induced hyperalgesia in mice, mainly through central sensitization and the elevation of spinal ROS is most likely due to increased production of mitochondrial superoxides in dorsal horn neurons. \r\nThis study also investigated the role of mitochondrial antioxidant SOD2 in pain. Experiments were done to measure spinal levels of SOD2 protein and activity, inactivated SOD2 protein, and ROS accumulating dorsal horn cells after capsaicin injection to mouse foot with or without ROS scavengers. The capsaicin-induced hyperalgesia was determined in mice after manipulating SOD levels. Results showed that following capsaicin treatment, spinal levels of SOD2 activity were decreased, inactivated SOD2 proteins were increased, but total SOD2 proteins were unchanged. These changes were reversed with ROS scavengers. Mice showed enhanced or reduced hyperalgesia with decreased or increased SOD2 levels, respectively. The number of ROS accumulating cells was increased in SOD2KO mice but decreased in SOD2Tg mice. The data suggest that SOD2 activity levels determine the ROS accumulation, which in turn determines the levels of central sensitization and capsaicin-induced secondary hyperalgesia. Therefore, this study suggests a therapeutic potential of targeting SOD2 in persistent pain conditions. \r\n\r\n\r\n