Pain is defined as an unpleasant sensation and emotional experience associated with actual or potential tissue injury. Everyone at some point has experienced a painful sensation. Pain can cause unwanted physical, emotional and social anguish throughout one's daily life. According to the American Chronic Pain Association, pain is the number one cause of adult disability in the U.S. costing an estimated $80 billion annually in medical bills and lost productivity. Unfortunately, over the past decades, our understanding of pain mechanisms and efforts to control pain are not adequate. So as a consequence, current medications for pain managements, especially that for chronic pain, are not efficacious, and often associated with intolerable side effects. Therefore, target specific, mechanism based therapeutic medications for effective, and safe pain control is an unmet medical need. In my dissertation I have focused on characterizing the role of two proteins involved in mediating neuropathic pain, a form of chronic pain. I provide evidence showing that the auxiliary subunit of the voltage gated calcium channel alpha 2 delta-1 protein is upregulated in the dorsal spinal cord (DSC) due to peripheral nerve injury. This upregulation can be pervented by blocking ectopic discharges at the site of injury or using intrathecal calcium channel alpha 2 delta-1 antisense oligodeoxynucleotide preemptively. This inhibition of calcium channel alpha 2 delta-1 levels in DSC result in delay in the development of neuropathic pain, suggesting elevated levels of calcium channel alpha 2 delta-1 in the DSC mediates the initiation of peripheral nerve injury induced neuropathic pain. I have also determined that the calcium channel alpha 2 delta-1 protein plays a role in central neuropathic pain. I observed an upregulation of the calcium channel alpha 2 delta-1 protein in the DSC of spinal cord injured (SCI) rats with neuropathic pain states, and both neuropathic pain states and calcium channel alpha 2 delta-1 protein levels could be reversed by intrathecal calcium channel alpha 2 delta-1 antisense oligodeoxynucleotides. Lastly, I contributed to identifying thrombospondin-4 (TSP4) protein, a synapse inducer, as a novel mediator in the development of neuropathic pain. Similar to the calcium channel alpha 2 delta-1 protein, TSP4 protein levels were also upregulated in DSC of peripheral nerve injury induced neuropathic pain models that correlated with pain states, . Various pharmacological agents could alter both the TSP4 levels in DSC and behavioral hypersensitivity supporting the notion that TSP4 plays a novel role in neuropathic pain. I was also able to show using immunohistchemistry that enhanced levels of TSP4 colocalized with calcium channel alpha 2 delta-1 and presynaptic marker synaptic vesicle-2 protein (sv2) in the DSC, suggesting that interaction of these two proteins plays a possible role in spinal synaptogenesis, leading to neuropathic pain transmission. These findings provide a greater understanding in the mechanism of chronic pain, which can ultimately contribute to development of new target specific medications for alleviating this debilitating disease state.