Browsing by Subject "central sensitization"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Critical role of ROS in capsaicin-induced hyperalgesia(2008-01-28) Erica Susanne Schwartz; Jin Mo Chung, PhD; William Willis, MD PhD; Kyungsoon Chung, PhD; Giulio Taglialatela, PhD; Eric Klann, PhDRecent 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\nItem Neuropathic pain and the inhibition of learning within the spinal cord(Texas A&M University, 2004-09-30) Ferguson, Adam RichardPrior work from our laboratory has shown that the spinal cord is capable of supporting a simple form of instrumental (response-outcome) learning. In a typical experiment, animals are given a spinal transection at the second thoracic vertebra, and tested 24 h after surgery. If animals are given shock when their leg is in a resting position (controllable shock), they quickly learn to maintain the leg in a flexed position, thereby minimizing shock exposure. Animals exposed to shock that is independent of leg position (uncontrollable shock) fail to learn. This learning deficit can be induced by as little as 6 minutes of shock to either limb or to the tail, and lasts for up to 48 h. The aim of this dissertation was to explore whether the deficit shares behavioral features and pharmacological mechanisms similar to those involved in the induction of neuropathic pain. Work within the pain literature has identified a spinal hyperexcitability that is induced by intense stimulation of pain fibers. This phenomenon, known as central sensitization, is characterized by an increase in tactile reactivity (allodynia) that can be induced by shock or peripheral inflammation. Pharmacological findings have revealed that central sensitization depends on the activation of the N-methyl-D-aspartate (NMDA) and group I metabotropic glutamate receptors (mGluRs). Experiment 1 showed that uncontrollable shock induces a tactile allodynia similar to that observed in central sensitization. Experiment 2 showed that peripheral inflammation caused by a subcutaneous injection of formalin generates a dose-dependent deficit. Experiment 3 indicated that the formalin-induced deficit was observed 24 h after delivery of the stimulus. Experiments 4-8 revealed that the NMDA and group I mGluRs are involved in the deficit. The NMDA receptor was found to be necessary (Experiment 4), but only sufficient to induce a deficit at neurotoxic doses (Experiment 5). Both of the group I mGluRs (subtypes, mGluR1 and mGluR5) were found to be necessary (Experiments 6 & 7). A general group I mGluR agonist summated with a subthreshold intensity of shock to produce a robust deficit (Experiment 8), suggesting shock and mGluR activation produce a deficit through a common mechanism.