Pain Input After Spinal Cord Injury (SCI) Undermines Long-Term Recovery and Engages Signal Pathways That Promote Cell Death

Abstract

Pain (nociceptive) input caudal to a spinal contusion injury increases tissue loss and impairs long-term recovery. It was hypothesized that noxious stimulation has this effect because it engages unmyelinated pain (C) fibers that produce a state of over-excitation in central pathways. The present article explored this issue by assessing the effect of capsaicin, which activates C-fibers that express the transient receptor potential vanilloid receptor-1 (TRPV1). Rats received a lower thoracic (T11) contusion injury and capsaicin was applied to one hind paw the next day. For comparison, other animals received noxious electrical stimulation at an intensity that engages C fibers. Both forms of stimulation elicited similar levels of c-fos mRNA expression, a cellular marker of nociceptive activation, and impaired long-term behavioral recovery. Cellular assays were then performed to compare the acute effect of shock and capsaicin treatment. Both forms of noxious stimulation increased expression of tumor necrosis factor (TNF) and caspase-3, which promotes apoptotic cell death. Shock, but not capsaicin, enhanced expression of signals related to pyroptotic cell death [caspase-1, inteleukin-1 beta (IL-1ß)]. Pyroptosis has been linked to the activation of the P2X7 receptor and the outward flow of adenosine triphosphate (ATP) through the pannexin-1 channel. Blocking the P2X7 receptor with Brilliant Blue G (BBG) reduced the expression of signals related to pyroptotic cell death in contused rats that had received shock. Blocking the pannexin-1 channel with probenecid paradoxically had the opposite effect. BBG enhanced long-term recovery and lowered reactivity to mechanical stimulation applied to the girdle region (an index of chronic pain), but did not block the adverse effect of nociceptive stimulation. The results suggest that C-fiber input after injury impairs long-term recovery and that this effect may arise because it induces apoptotic cell death.

Engaging pain fibers after a spinal cord injury fosters hemorrhage and expands the area of secondary injury

“…Peripheral application of the irritant capsaicin 24 h after a spinal contusion injury engages an acute up-regulation of signal pathways associated with cell death and impairs long-term recovery (Turtle et al, 2018). The present experiment examines whether this treatment also promotes hemorrhage after injury and how this effect varies over time.…”

“…Elsewhere, we have shown that noxious stimulation can activate signal pathways linked to neural over-excitation and cell death (e.g., caspase 1, 3 and 8) (Ferguson et al, 2008; Garraway et al, 2014; Huie et al, 2015; Turtle et al, 2018). These processes could also contribute to the breakdown of the BSCB by initiating cell death within endothelial cells or indirectly by depleting energy stores (ATP).…”

“…We chose these two forms of stimulation to demonstrate the generality of our results. Both forms of stimulation have been shown to sensitize nociceptive processing and impair long-term recovery (Grau et al, 2004; Huang et al, 2016; Turtle et al, 2018). They differ in duration, temporal character (phasic versus tonic), and site of application.…”

“…Application of capsaicin, which engages C-fibers that express the transient receptor potential cation channel subfamily V member 1 (TRPV1), to one hind paw has the same effect (Hook et al, 2008). In animals that have received a contusion injury of the lower thoracic spinal cord, engaging pain fibers below the injury expands tissue loss and undermines long-term locomotor recovery (Grau et al, 2004; Turtle et al, 2018). Nociceptive stimulation also fosters the development of spasticity, impairs the recovery of bladder function, and enhances the development of chronic pain (Grau et al, 2004, 2017; Garraway et al, 2014).…”

“…Nociceptive stimulation also fosters the development of spasticity, impairs the recovery of bladder function, and enhances the development of chronic pain (Grau et al, 2004, 2017; Garraway et al, 2014). These adverse effects are most evident when stimulation occurs within a few days of injury (Grau et al, 2004) and are associated with the activation of pro-inflammatory cytokines [e.g., tumor necrosis factor (TNF), interleukin-1ß (IL-1ß), and interleukin-18 (IL-18)] and indices of cell death (e.g., caspase 1, 3, and 8) (Garraway et al, 2014; Turtle et al, 2018).…”