Nociceptive (Pain) Input After Spinal Cord Injury (SCI) Enhances Secondary Injury: Identifying Treatments That Can Be Translated to Clinical Practice
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Background. Using an animal model, we have shown that nociceptive (pain) input after spinal cord injury (SCI) amplifies secondary injury and undermines long-term recovery. These observations are important, because SCI is often accompanied by additional tissue damage (polytrauma) that provides a source of nociceptive input. In prior studies, these effects were examined using intermittent electrical stimulation to engage sensory fibers. Just 6 minutes of stimulation at an intensity that activates unmyelinated pain (C) fibers induces a form maladaptive plasticity that sensitizes behavioral reactivity and inhibits adaptive learning. In contused rats, a brief period of noxious electrical stimulation undermines long-term behavioral recovery, enhances the development of pain and spasticity, and increases tissue loss (secondary injury) at the site of injury.The current proposal is motivated by four recent discoveries. First, we found that nociceptive input induces a breakdown in the blood-spinal cord barrier (BSCB) that allows blood to infiltrate spinal cord tissue. Because red blood cells are neurotoxic, this hemorrhage augments cell death (secondary injury). Second, we found that the adverse effect of noxious electrical stimulation can be prevented using a local anesthetic (lidocaine), applied by means of a lumbosacral puncture. Licodaine completely blocked the development of acute hemorrhage and the activation of pro-inflammatory cytokines. Most importantly, it also blocked the adverse effect nociceptive stimulation has on long-term recovery. Third, we showed that the development of hemorrhage, and the adverse effects of nociceptive stimulation, involve brain-dependent processes. This was shown by contusing the spinal cord in the lower (T10-T11) region and then cutting communication with the brain by means of a rostral (T2) transection. The transection blocked the effect of nociceptive stimulation on hemorrhage and the activation of proteins related to cell death/inflammation. To further explore the potential role of brain systems, we assessed the effect of placing animals in a state analogous to a medically induced coma, using the general anesthetic pentobarbital. Pentobarbital blocked the adverse effect of electrical stimulation on acute injury/hemorrhage and long-term recovery. Finally, we evaluated whether other forms of noxious stimulation impact long-term recovery. This issue was explored using the irritant capsaicin, which selectively engages C-fibers that express the TRPV1 receptor. Peripheral application of capsaicin impaired long-term recovery in contused rats. Hypotheses. It is clear that nociceptive input after injury expands the area of secondary injury and undermines long-term recovery. New findings show that this effect is due to the acute breakdown of the BSCB, an effect we hypothesize is linked to the induction of progressive hemorrhagic necrosis (PHN). The present proposal moves this line of research from a model paradigm, wherein sensory fibers are engaged for a brief period of time with electrical stimulation, to a clinically relevant preparation in which C-fibers are tonically activated using a peripheral irritant (capsaicin). Most importantly, we explore how the adverse effects of pain input can be blocked using treatments that can be readily translated to practice. Based on new data, demonstrating that spared fibers and brain systems play a key role, we seek to show that maintaining a medically induced coma can reduce acute tissue loss during the acute stage of injury. We further hypothesize that inhibiting communication to the brain via a pharmacological transection can prevent nociception-induced hemorrhage.Aims. Aim 1 will characterize the duration of capsaicin-induced hemorrhage, the circumstances under which it affects tissue sparing, the role of brain systems and PHN, and whether similar effect are observed in males and females. Aim 2 will examine whether general anesthesia has a beneficial effect if given after injury or nociceptive stimulation and confirm that this treatment is effective when pain fibers are driven for an extended period (via capsaicin). Aim 3 will compare the effect of lidocaine applied caudal to injury (T12) versus rostrally (T4) and will explore treatment effectiveness when given after surgery or prior to capsaicin.Study Design. All of the experiments will use balanced factorial designs. Locomotor and cardiac function will be assessed in vivo. The impact of nociceptive input on injury will be assessed using protein assays (Western blotting for ligands related to hemorrhage, cell death and inflammation; immunoprecipitation to assess a marker of PHN [Sur1-Trpm4]); and microscopy (to explore hemorrhage extent and capillary fragmentation).Impact. It is clear that nociceptive input after injury can increase tissue loss, increase the incidence of chronic pain, and undermine the recovery of locomotor function. Our new work has identified the mechanisms that underlie this effect and suggests treatments that can be readily translated to clinical practice â€“ procedures that could be performed en route to reduce acute tissue loss after injury and promote long-term recovery.Military Relevance. Events that lead to SCI in a military situation are particularly likely to produce polytrauma, providing a source of nociceptive input that will amplify tissue loss at the site of injury. By showing how the adverse effects of nociceptive input can be blocked to improve long-term outcome using already approved procedures, the proposed experiments will provide the data needed to rapidly transition the treatments to clinical practice.