Trauma is the most common cause of spinal cord-related disability in the U.S. Tissue damage after spinal trauma may result from secondary injury caused by endogenous factors. One such factor includes the release or activation of opiate peptides. For example, dynorphin A peptides contribute to secondary tissue damage after spinal cord injury through both opiate-receptor mediated and non-opioid mechanisms. Consequently, we will use intrathecal injection of dynorphin in the rat to model secondary spinal cord injury. Our goal is to characterize the post-treatment neuroprotective effects of drugs that address specific mechanisms of neuronal damage. These include both excitatory and inhibitory neurotransmitter systems and secondary responses triggered by ischemia. We will assay excitatory amino acid antagonists, opiate antagonists and drugs affecting GABA pathways in the spinal cord. Because localized ischemia often results from secondary processes, we will test antagonists to this effect and agents known to attenuate ischemia-induced lipid peroxidation. Our methods consist of surgically implanting a cannula in each rat through which we inject drugs directly onto the spinal cord. We will assess a neuroprotective action behaviorally (tail-flick reflex), electrophysiologically (C-fiber evoked reflex) and histologically. We will challenge the secondary processes initiated by dynorphin injection with potential antagonists in a range of doses as a pretreatment to obtain an ED50. In post-treatment studies we will use the most potent drugs alone and in combination to ascertain the time window of the neuroprotective effect. We will use isobolographic analysis to characterize the effect of the combination in relation to the effect of each drug individually. With this experimental approach we should be able to explore mechanisms of secondary injury leading to cell death and characterize therapeutic agents for human trials in acute spinal cord injury.
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