Spinal cord injury (SCI) produces a permanent loss of function below the level of damage. In addition, more than 80% of SCI patients report the development of horribly debilitating neuropathic pain (NP) that further robs the individual of life quality. NP can be an almost constant pathological companion for these individuals and represents a significant cause of suicide in the chronic SCI population. Unfortunately, there are few therapeutic options available to treat NP with a low percentage of individuals reporting treatment efficacy. One possible explanation for the low number of effective treatment options is our poor understanding of the mechanisms that initiate and potentially maintain NP in chronic SCI. Inflammation represents one possible mechanism to elicit NP in the days to weeks following SCI. However, inflammation has previously been considered to be transient, with mechanisms maintaining chronic NP unclear. Our published research suggests, however, that inflammation can be detected long after the initial injury in a clinically-relevant model of rat SCI. We detect the presence of inflammatory metabolites of arachidonic acid, particularly prostaglandins and leukotrienes, produced by cyclooxygenase and lipoxygenase enzymes, respectively. FDA-approved non-steroidal inflammatory (NSAIDs) drugs such as ibuprofen have been tried as analgesics for SCI-NP, but are ineffective. Our detection of elevated intraspinal prostaglandins AND leukotrienes suggests a possible explanation for the failure of ?over the counter? NSAIDs in treating NP. Studies have shown that the targeting of only one metabolic pathway, for instance, the cyclooxygenase pathway that generates prostaglandins, results in a ?shunting? of the arachidonic acid into the sister lipoxygenase pathway that produced leukotrienes; the end result being a net ?gain? of pro-inflammatory mediators (in this specific example, increased leukotrienes). We demonstrated that delayed treatment with a novel dual inhibitor of both cyclooxygenase AND 5-lipoxygenase enzymes successfully reduced NP in rats with chronic SCI. We subsequently demonstrated that this experimental drug reduced both prostaglandins and leukotrienes if administered in the acute phase of injury, resulting in significant locomotor recovery. Unfortunately, this drug is not FDA-approved. Our current goal is to test combinations of FDA- approved inhibitors of cyclooxygenase AND 5-lipoxygenase to determine: 1) if combinations of these two classes of inhibitors are as effective at treating or permanently blocking chronic NP as the previously tested experimental dual-inhibitory drug, and 2) whether such treatment resolves the chronic pro-inflammatory state as evidenced by reduced prostaglandin and leukotriene biosynthesis. As the FDA-approval process can require decades to move a drug from bench to bedside, the effective translation of already-FDA-approved drugs to new tasks, such as the treatment of neuropathic pain could significantly reduce time needed for subsequent clinical evaluation and use. Targeting prostaglandin AND leukotriene production to treat chronic NP with FDA-approved inhibitors would represent a novel therapeutic approach and would represent a critical advancement in care for the chronic SCI community.

Public Health Relevance

The majority of individuals living with a spinal cord injury experience horribly debilitating neuropathic pain that is resistant to therapeutic treatment. We recently demonstrated the presence of arachidonic acid-derived pro-inflammatory mediators, prostaglandins and leukotrienes, produced through both the cyclooxygenase and lipoxygenase pathwaysvin the spinal cords of rats with chronic spinal cord injuries. The presence of these two types of pro-inflammatory mediators suggest a profound state of ongoing inflammation in chronic spinal cord injury. We subsequently demonstrated that a delayed but sustained treatment with a novel dual inhibitor of cyclooxygenase and lipoxygenase pathways significantly reduced chronic neuropathic pain. As this drug is not FDA-approved, our goal in this proposal is to develop a translational treatment for spinal cord injury-dependent neuropathic pain using a combination of FDA-approved inhibitors of both cyclooxygenase and lipoxygenase pathways.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology C (NURC)
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G V Sonny Montgomery VA Medical Center
United States
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