Spinal cord injuries (SCI) are frequently accompanied by additional tissue damage (polytrauma) that
activates 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. The
expansion 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 channel
found on the endothelial cells that form the BSCB. Engaging this channel allows excessive sodium to enter the
cell, inducing oncotic cell death, and a breakdown (capillary fragmentation) of the BSCB. This phenomenon is
known 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 hypothesized
that greater PHN will be observed soon after a light to moderate injury, that the effect will be observed in both
male and female rats, and that the effect of nociceptive stimulation is regulated by learning (controllability). The
experiments will use cellular assays (Western blotting) and immunohistochemistry to explore how these
variables influence the development of hemorrhage and the cell types affected. To explore the link to
hypertension, 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 is
engaged by capsaicin. The experiments will test whether these fibers are necessary and sufficient to induce
PHN after SCI and the role of the neurotransmitter substance P. These issues will be addressed by chemically
lesioning 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 this
channel 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. Preliminary
data 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 the
integrity of the BSCB and the effect of hypertension. The latter will be manipulated using drug treatments that
induce, or block, this effect. It is suggested that pharmacologically blocking the rise in blood pressure will
attenuate 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 thereby
foster long-term recovery. It is proposed that blocking the breakdown of the BSCB or nociception-induced
hypertension will reduce secondary injury and promote recovery.