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.

Public Health Relevance

Tens of thousands of individuals experience a spinal cord injury (SCI) each year. These injuries are often accompanied by additional damage (polytrauma) that provides a source of pain (nociceptive) input that fuels processes at the site of injury that augment tissue loss (secondary injury) and undermine long-term recovery. The proposed experiments relate the nociception-induced loss of tissue to a break down in the blood spinal cord barrier and increased blood pressure (hypertension), and suggest that halting these processes will lessen secondary injury and promote recovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS104422-02
Application #
9747362
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jakeman, Lyn B
Project Start
2018-08-01
Project End
2023-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
020271826
City
College Station
State
TX
Country
United States
Zip Code
77845