Research Project: Nociceptive (Pain) Input After Spinal Cord Injury (SCI) Enhances Secondary Injury: Identifying Treatments That Can Be Translated to Clinical Practice
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Spinal cord injury (SCI) brings a high cost, both in terms of medical treatment and the individual's long-term wellbeing. The degree of injury depends upon both the initial tissue damage (primary injury) and the subsequent loss of tissue in the surrounding region (secondary injury). It is now recognized that nearly half the cell loss is due to secondary injury. Because the processes that contribute to secondary injury unfold over the course of hours to days, it represents a treatable clinical target.
Our work has shown that pain input after injury can expand the area of secondary injury, amplifying tissue loss and undermining long-term recovery. This is an important observation, because many spinal cord injuries, especially in military action, are accompanied by additional tissue damage (polytrauma) that will engage pain fibers. If these wounds are at, or below, the level of the SCI, the sensory signals may generate little ¬"psychology" pain (because neural transmission to the brain is disrupted). The sensory signals can, however, still engage neurobiological processes within the spinal cord that influence tissue loss. Of particular concern, our work has shown that incoming pain signals can drive a state of over-excitation that fuels cell death and leads to a breakdown in the blood-spinal cord barrier (BSCD). This barrier normally keeps red blood and other cells from infiltrating the neural tissue (while allowing essential nutrients to pass). When the barrier is broken, hemoglobin leaks out of the blood vessels into the surrounding tissue, causing an area of hemorrhage that kills neurons and non-neuronal cells (e.g., the oligodendrocytes that ensheathe axons within the white matter). This, in conjunction with an amplified immune response, could feed a rise in pro-inflammatory cytokines that leads to further cell loss. Acting together, the hemorrhage will expand the region of secondary injury and thereby undermine long-term recovery.
Pain input after SCI appears to fuel hemorrhage in two ways. One is by engaging a signal pathway that leads to the death of the endothelial cells that form the BSCD. This process is known as progressive hemorrhagic necrosis. It can be identified by the activation of particular proteins (e.g., Sur1-Trpm4) and the fragmentation of capillaries. The second key process involves an increase in blood pressure (hypertension). Interestingly, this cardiac event is not due to a local (spinally-mediated) effect (as occurs, for example, in autonomic dysreflexia). Instead, new research has revealed that pain-induced hypertension and hemorrhage depend upon brain systems. Supporting this, we have shown that cutting the surviving fibers blocks the adverse effect of noxious stimulation. Inhibiting brain function (via a medically induced coma) also has a protective effect. These surprising data suggest that secondary tissue loss after SCI depends, in part, on brain systems.
Interestingly, blocking "psychological" pain with an opiate analgesic (morphine) does not counter the adverse effect of stimulation. This suggests that the damage is due to engaging the underlying neural processes, not the resultant experience of pain. New work has shown that this neural activity can be blocked by inhibiting cellular activity within the spinal cord using the local anesthetic lidocaine.
A limitation of past studies is that sensory fibers were artificially driven using a brief period (6 minutes) of intermittent electrical stimulation. New data has shown that selectively engaging pain fibers, by applying the irritant capsaicin (the active ingredient of chili peppers), leads to a prolonged period of hemorrhage after SCI and undermines long-term recovery. The present proposal will use this treatment to explore the circumstances under which pain input affects tissue loss and the neurobiological mechanisms that underlie this effect.
More importantly, we seek to show how two treatments can be used to reduce the adverse effects of pain input on injury. We propose that inducing a coma-like state with pentobarbital will attenuate hemorrhage after injury. We also propose that blocking neural conduction along spared fibers, by slowing infusing lidocaine into the spinal cord above the injury, will reduce capsaicin-induced hemorrhage. The benefits of these manipulations will be evident from a reduction of hemoglobin infiltration and reduced expression of proteins associated with cell death and inflammation.
We focus on the beneficial effects of general anesthesia and spinally applied lidocaine because these treatments can be readily translated to clinical practice. Indeed, our work suggests that epidural lidocaine given soon after injury could provide both relief from pain and halt the pain-induced expansion of secondary injury. Because nearly all military-related SCI involve polytrauma, this treatment could become a standard of care. This treatment is routinely used to attenuate pain during child birth. Risks are minimal. The potential benefits are high. Given additional empirical data, mapping out treatment effectiveness, the procedures we explore could be rapidly transitioned to humans. The heuristic is that, if we can spare just 10% of the ascending/descending fibers, the person will walk out of the hospital. Implementing these procedures could help meet this goal, and thereby dramatically improve long-term quality of life.
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