Abstract
Pain (nociceptive) input caudal to a spinal contusion injury can undermine long-term recovery and increase tissue loss (secondary injury). Prior work suggests that nociceptive stimulation has this effect because it fosters the breakdown of the blood-spinal cord barrier (BSCB) at the site of injury, allowing blood to infiltrate the tissue. The present study examined whether these effects impact tissue rostral and caudal to the site of injury. In addition, the study evaluated whether cutting communication with the brain, by means of a rostral transection, affects the development of hemorrhage. Eighteen hours after rats received a lower thoracic (T11–12) contusion injury, half underwent a spinal transection at T2. Noxious electrical stimulation (shock) was applied 6 h later. Cellular assays showed that, in non-transected rats, nociceptive stimulation increased hemoglobin content, activated pro-inflammatory cytokines and engaged signals related to cell death at the site of injury. These effects were not observed in transected animals. In the next experiment, the spinal transection was performed at the time of contusion injury. Nociceptive stimulation was applied 24 h later and tissue was sectioned for microscopy. In non-transected rats, nociceptive stimulation increased the area of hemorrhage and this effect was blocked by spinal transection. These findings imply that the adverse effect of noxious stimulation depends upon spared ascending fibers and the activation of rostral (brain) systems. If true, stimulation should induce less hemorrhage after a severe contusion injury that blocks transmission to the brain. To test this, rats were given a mild, moderate, or severe, injury and electrical stimulation was applied 24 h later. Histological analyses of longitudinal sections showed that nociceptive stimulation triggered less hemorrhage after a severe contusion injury. The results suggest that brain-dependent processes drive pain-induced hemorrhage after spinal cord injury (SCI).
Highlights
Spinal cord injuries are frequently accompanied by additional tissue damage that can provide a source of pain input after injury (Saboe et al, 1991; Chu et al, 2009)
Spinal Transection Blocks the Effect of Nociceptive Stimulation on Hemorrhage
We have suggested that electrical stimulation has this effect because it engages pain fibers
Summary
Spinal cord injuries are frequently accompanied by additional tissue damage (polytrauma) that can provide a source of pain (nociceptive) input after injury (Saboe et al, 1991; Chu et al, 2009) This is clinically important because research has shown that nociceptive stimulation caudal to spinal cord injury (SCI) can sensitize pain circuits, impair adaptive plasticity, increase tissue loss (secondary injury) at the site of injury, and undermine long-term recovery (Grau et al, 2017). Pain fibers are engaged using intermittent electrical stimulation (shock) applied at a intensity and duration known to impair adaptive plasticity in spinally transected animals (Grau et al, 1998; Crown et al, 2002) Using this paradigm, we have shown that just 6 min of uncontrollable shock applied to the tail or hind leg a day after injury impairs long-term recovery and increases tissue loss. The acute effect of engaging nociceptive fibers has been linked to the expression of pro-inflammatory cytokines [e.g., tumor necrosis factor (TNF), interleukin-1β (IL-1β), and IL-18] and the activation of cellular signals (e.g., caspase 1, 3, 8) related to cell death (Garraway et al, 2011, 2014; Lossi et al, 2015; Grau and Huang, 2018; Turtle et al, 2018)
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