Acute Pain after Spinal Cord Injury: Impaired Recovery through Inflammation, Cell Death, and Hemorrhage

Over 90% of spinal cord injuries are caused by traumatic accidents and are often associated with secondary tissue damage that can provide a source of continued pain input. Previous work has shown that nociceptive stimulation (pain input) soon after spinal cord injury increases lesion volume, undermines recovery of locomotor function, and induces signs of neuropathic pain. In previous studies, rats received six minutes of intermittent electrical stimulation to the tail twenty-four hours after a moderate lower thoracic spinal cord contusion. The goals of this dissertation were to examine mechanisms that underlie nociceptive stimulation-induced impaired recovery, and to develop a therapeutic strategy that might be capable of reversing the negative effects of acute pain in patients with spinal cord injury. A clinically relevant spinal cord contusion injury model was used to examine functional outcomes, molecular markers, and histopathological changes associated with acute pain after spinal cord injury. Either pharmacologic or electrical C fiber stimulation after injury was sufficient to undermine functional outcomes. Further, both stimulation paradigms increased signs of inflammation, apoptosis, pyroptosis, and hemorrhage. Hemorrhage was associated with increased formation of SUR1-TRPM4 channels, which is a known pathognomonic indicator of progressive hemorrhagic necrosis. Treatments that target pathologic purinergic signaling to inhibit pyroptosis reduced inflammation, but did not improve functional outcomes. Further, standard treatment with systemic morphine had no impact on acute pain-induced effects. In contrast, spinal block with lidocaine blocked the inflammation, apoptosis, pyroptosis, hemorrhage, and impaired functional recovery associated with acute pain. Experiment results highlight the detrimental impact of acute pain soon after spinal cord injury. Progressive hemorrhagic necrosis was enhanced by nociceptive stimulation and likely triggers increased cell death through a combination of pyroptosis and apoptosis. Further, current clinical treatments for pain management after trauma proved ineffective at reversing the impact of acute pain. However, epidural lidocaine successfully reversed all signs of impaired recovery. Thus, for patients with spinal cord damage, use of lidocaine spinal blocks soon after injury might provide an effective alternative therapy for treatment of acute pain