Nociceptive Input After Spinal Cord Injury (SCI) Expands the Region of Secondary Injury and Undermines Long-Term Recovery
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Spinal cord injuries (SCI) are frequently accompanied by additional tissue damage (polytrauma) thatactivates pain (nociceptive) fibers. If this nociceptive input drives neurons within the spinal cord at, or below,the site of injury, it can over-excite neurons, enhance cell death, and undermine long-term recovery. Theexpansion of tissue loss (secondary injury) has been related to a disruption in the blood spinal cord barrier(BSCB). Preliminary data show that nociceptive stimulation increases the expression of Sur1-Trpm4, a channelfound on the endothelial cells that form the BSCB. Engaging this channel allows excessive sodium to enter thecell, inducing oncotic cell death, and a breakdown (capillary fragmentation) of the BSCB. This phenomenon isknown as progressive hemorrhage necrosis (PHN). At the same time, there is a rise in blood pressure(hypertension) that fuels a surge of blood (hemorrhage) into the spinal cord, triggering further cell death. Aim 1 will explore the circumstances under which nociceptive stimulation triggers PHN. It is hypothesizedthat greater PHN will be observed soon after a light to moderate injury, that the effect will be observed in bothmale and female rats, and that the effect of nociceptive stimulation is regulated by learning (controllability). Theexperiments will use cellular assays (Western blotting) and immunohistochemistry to explore how thesevariables influence the development of hemorrhage and the cell types affected. To explore the link tohypertension, blood pressure and heart rate will also be monitored. Aim 2 will examine the role of unmyelinated pain (C) fibers that contain the TRPV1 receptor, which isengaged by capsaicin. The experiments will test whether these fibers are necessary and sufficient to inducePHN after SCI and the role of the neurotransmitter substance P. These issues will be addressed by chemicallylesioning these fibers, activating them using capsaicin, and microinjecting substance P into the spinal cord. Aim 3 will explore how nociceptive input triggers Sur1-Trpm4 expression. It is proposed that blocking thischannel will attenuate nociception-induced PHN and thereby enhance tissue sparing and long-term recovery. Aim 4 evaluates how changes in blood pressure influence the development of hemorrhage. Preliminarydata show that a rostral spinal cord transection blocks nociception-induced hypertension in contused rats.Using this experimental manipulation, the proposed experiments will evaluate how nociceptive input affects theintegrity of the BSCB and the effect of hypertension. The latter will be manipulated using drug treatments thatinduce, or block, this effect. It is suggested that pharmacologically blocking the rise in blood pressure willattenuate nociception-induced hemorrhage and its adverse effect on long-term recovery. The long-term goal of this work is to reduce the development of secondary injury after SCI and therebyfoster long-term recovery. It is proposed that blocking the breakdown of the BSCB or nociception-inducedhypertension will reduce secondary injury and promote recovery.