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

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.

[1]  C. Beyer,et al.  Inflammasome: Its role in traumatic brain and spinal cord injury , 2018, Journal of cellular physiology.

[2]  Adam R Ferguson,et al.  Impact of Behavioral Control on the Processing of Nociceptive Stimulation , 2012, Front. Physio..

[3]  W. Shao,et al.  The Caspase-1 Digestome Identifies the Glycolysis Pathway as a Target during Infection and Septic Shock*♦ , 2007, Journal of Biological Chemistry.

[4]  K. H. Lee,et al.  Intermittent noxious stimulation following spinal cord contusion injury impairs locomotor recovery and reduces spinal brain-derived neurotrophic factor–tropomyosin-receptor kinase signaling in adult rats , 2011, Neuroscience.

[5]  J. P. de Rivero Vaccari,et al.  Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[6]  Adam R Ferguson,et al.  Instrumental learning within the spinal cord: IV. Induction and retention of the behavioral deficit observed after noncontingent shock. , 2002, Behavioral neuroscience.

[7]  R. W. Keane,et al.  Pannexin: From discovery to bedside in 11±4 years? , 2012, Brain Research.

[8]  L. A. Swayne,et al.  The emerging Pannexin 1 signalome: a new nexus revealed? , 2014, Front. Cell. Neurosci..

[9]  J. P. de Rivero Vaccari,et al.  Therapeutics targeting the inflammasome after central nervous system injury. , 2016, Translational research : the journal of laboratory and clinical medicine.

[10]  J. Simard,et al.  Endothelial sulfonylurea receptor 1-regulated NC Ca-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury. , 2007, The Journal of clinical investigation.

[11]  B. Cookson,et al.  Caspase‐1‐dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages , 2006, Cellular microbiology.

[12]  J. Wyndaele,et al.  Incidence, prevalence and epidemiology of spinal cord injury: what learns a worldwide literature survey? , 2006, Spinal Cord.

[13]  G. López-Castejón,et al.  Caspase-1: is IL-1 just the tip of the ICEberg? , 2012, Cell Death and Disease.

[14]  Adam R Ferguson,et al.  Uncontrollable stimulation undermines recovery after spinal cord injury. , 2004, Journal of neurotrauma.

[15]  J. Grau,et al.  Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization , 2016, Experimental Neurology.

[16]  J W Grau,et al.  Instrumental learning within the spinal cord: I. Behavioral properties. , 1998, Behavioral neuroscience.

[17]  J. Grau,et al.  Spinal glia modulate both adaptive and pathological processes , 2009, Brain, Behavior, and Immunity.

[18]  Adam R Ferguson,et al.  Instrumental learning within the spinal cord: V. Evidence the behavioral deficit observed after noncontingent nociceptive stimulation reflects an intraspinal modification , 2003, Behavioural Brain Research.

[19]  Adam R Ferguson,et al.  The impact of morphine after a spinal cord injury , 2007, Behavioural Brain Research.

[20]  D. Basso,et al.  A sensitive and reliable locomotor rating scale for open field testing in rats. , 1995, Journal of neurotrauma.

[21]  Adam R Ferguson,et al.  Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: Role of tumor necrosis factor alpha and apoptosis , 2014, PAIN®.

[22]  J. Grau,et al.  Peripheral inflammation undermines the plasticity of the isolated spinal cord. , 2008, Behavioral neuroscience.

[23]  M. Devivo,et al.  Causes and costs of spinal cord injury in the United States , 1997, Spinal Cord.

[24]  J. Grau,et al.  When Pain Hurts: Nociceptive Stimulation Induces a State of Maladaptive Plasticity and Impairs Recovery after Spinal Cord Injury. , 2017, Journal of neurotrauma.

[25]  Mark A. Murcko,et al.  Structure and mechanism of interleukin-lβ converting enzyme , 1994, Nature.

[26]  R. Joynes,et al.  Lipopolysaccharide induces a spinal learning deficit that is blocked by IL-1 receptor antagonism , 2007, Brain, Behavior, and Immunity.

[27]  T. Vanden Berghe,et al.  Major cell death pathways at a glance. , 2009, Microbes and infection.

[28]  J. Simard,et al.  Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury , 2012, Experimental Neurology.

[29]  J. Grau,et al.  An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury , 2011, Brain, Behavior, and Immunity.

[30]  J. Grau,et al.  Timing in the absence of supraspinal input I: Variable, but not fixed, spaced stimulation of the sciatic nerve undermines spinally-mediated instrumental learning , 2008, Neuroscience.

[31]  D. Gombos,et al.  Incidence, prevalence and epidemiology , 2013 .

[32]  H. Bramlett,et al.  A reassessment of P2X7 receptor inhibition as a neuroprotective strategy in rat models of contusion injury , 2012, Experimental Neurology.

[33]  J. Grau,et al.  Intrathecal morphine attenuates recovery of function after a spinal cord injury. , 2009, Journal of neurotrauma.

[34]  Adam R Ferguson,et al.  Maladaptive spinal plasticity opposes spinal learning and recovery in spinal cord injury , 2012, Front. Physio..

[35]  Adam R Ferguson,et al.  Nociceptive plasticity inhibits adaptive learning in the spinal cord , 2006, Neuroscience.

[36]  R. Ji,et al.  c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury? , 2009, The open pain journal.

[37]  R. Regan,et al.  Toxic effect of hemoglobin on spinal cord neurons in culture. , 1998, Journal of neurotrauma.

[38]  D. TurtleJoel,et al.  Pain Input Impairs Recovery after Spinal Cord Injury: Treatment with Lidocaine. , 2017 .

[39]  W. Willis.  Mechanisms of Central Sensitization of Nociceptive Dorsal Horn Neurons , 2001 .

[40]  R A Knight,et al.  Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 , 2011, Cell Death and Differentiation.

[41]  T. Yaksh,et al.  Quantitative assessment of tactile allodynia in the rat paw , 1994, Journal of Neuroscience Methods.

[42]  T. Takano,et al.  Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury , 2009, Proceedings of the National Academy of Sciences.

[43]  Adam R Ferguson,et al.  Glial Tumor Necrosis Factor Alpha (TNFα) Generates Metaplastic Inhibition of Spinal Learning , 2012, PloS one.

[44]  L. Bernier.  Purinergic regulation of inflammasome activation after central nervous system injury , 2012, The Journal of general physiology.

[45]  B. Cookson,et al.  Pyroptosis: host cell death and inflammation , 2009, Nature Reviews Microbiology.

[46]  Adam R Ferguson,et al.  Instrumental learning within the spinal cord: underlying mechanisms and implications for recovery after injury. , 2006, Behavioral and cognitive neuroscience reviews.

[47]  J. P. de Rivero Vaccari,et al.  A Molecular Platform in Neurons Regulates Inflammation after Spinal Cord Injury , 2008, The Journal of Neuroscience.

[48]  B. Cookson,et al.  Apoptosis, Pyroptosis, and Necrosis: Mechanistic Description of Dead and Dying Eukaryotic Cells , 2005, Infection and Immunity.

[49]  J. Grau,et al.  Instrumental learning within the spinal cord: III. Prior exposure to noncontingent shock induces a behavioral deficit that is blocked by an opioid antagonist , 2004, Neurobiology of Learning and Memory.

[50]  T. Kanneganti,et al.  The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation , 2016, The Journal of cell biology.

[51]  C. March,et al.  Molecular cloning of the interleukin-1 beta converting enzyme. , 1992, Science.

[52]  J. Grau.  Learning from the spinal cord: How the study of spinal cord plasticity informs our view of learning , 2014, Neurobiology of Learning and Memory.