An emerging concept in mechanisms that lead to neuropathic pain is elevated intracellular levels of reactiveoxygen species (ROS) in peripheral and central sensitization. The overall hypothesis of the PPG is thatROS act as key signaling molecules in concert with other signaling pathways involved in sensitization. Inthat context, the present proposal examines spinal cord injury (SCI) induced chronic central neuropathicpain (CNP). This is a major public health problem; consequently, an understanding of the mechanisms ofCNP will lead to opportunities for treatment of this terrible condition. We will use the rodent spinal cordcontusion model because this model best approximates human SCI. CNP in this model includes above level(C7/C8, forelimb innervation), at level (T8, trunk innervation) and below level (L4/L5, hindlimb innervation)pain-like behaviors seen clinically. CNP is thought to be generated in these different clinically relevantregions by different mechanisms. In this project, we will test the hypothesis that generation of ROS after SCIcontributes to central neuropathic pain by both peripheral and central sensitization via activatedcalcium/calmodulin kinase II (pCamKII) pathways. We will test the following specific aims:1) Determine the time course of development of CNP behavior in the rodent contusion model.2) Determine the time course of development of central and peripheral sensitization above level, at leveland below level after SCI.3) Test the sites of action of ROS inhibitors and the effects of these substances separately at those siteson CNP behaviors early and in chronic SC and on pCamKII expression levels.4) Determine the effect of ROS inhibition (by the most effective agent and route determined bybehavioral outcomes in Specific Aim 3) on central and peripheral sensitization early and in chronicSCI and on ROS expression levels.Outcome measures include behavior, electrophysiology, protein expression and immunocytochemistry. Ourresults will expand on Project 1 (ROS in peripheral sensitization after inflammation), Project 3 (role of ROSin C-fiber driven central sensitization) and Project 4 (role of ROS in amygdala and central sensitization) togive insight into mechanisms that provide common bases for development and maintenance of CNP andindicate therapeutically useful strategies for intervention in neuropathic and inflammatory pain syndromes.
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