Chronic or persistent pain is a difficult medical problem which affects millions of people in the U.S.because of no effective treatment. Therefore it is important to understand the mechanisms of persistentpain thereby allowing new treatment paradigms to be developed. An important discovery during the lastfew decades is that persistent pain is an abnormal state of the nervous system where neurons in theperiphery and the central nervous system are sensitized, called as peripheral and central sensitization,respectively. A recent emerging concept in persistent pain is that elevated levels of spinal reactive oxygenspecies (ROS) play a critical role in central sensitization. The focus of this proposal is the role of ROS incapsaicin induced secondary hyperalgesia due to central sensitization. The overall hypothesis is thatincreased production of mitochondrial superoxides in neurons in response to excessive nociceptive inputselevates ROS in the spinal cord. The elevated ROS then activate protein kinases, leading to increasedNMDA receptor activation and thus central sensitization.
Four specific aims are proposed to test thefollowing hypotheses in the mouse: 1) elevation of spinal ROS is critical for production of capsaicininducedsecondary hyperalgesia, thus removing ROS reduces pain; 2) elevation of spinal ROS is due toincreased production of superoxides in neurons in response to nociceptive afferent inputs; 3) superoxidedismutase (SOD) is a major mechanism for reducing spinal ROS effects; and 4) elevated spinal ROS willsensitize dorsal horn neurons by activating protein kinases, leading to enhanced phosphorylation ofNMDA receptors and thus central sensitization. The present proposal will test these hypotheses using amultidisciplinary approach. Successful completion of these aims will uncover important spinal mechanismsof persistent pain and may lead to the development of new analgesic drugs based on free radicalscavengers.
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