When Pain Hurts: Nociceptive Stimulation Induces a State of Maladaptive Plasticity and Impairs Recovery after Spinal Cord Injury

Abstract

Spinal cord injury (SCI) is often accompanied by other tissue damage (polytrauma) that provides a source of pain (nociceptive) input. Recent findings are reviewed that show SCI places the caudal tissue in a vulnerable state that exaggerates the effects nociceptive stimuli and promotes the development of nociceptive sensitization. Stimulation that is both unpredictable and uncontrollable induces a form of maladaptive plasticity that enhances nociceptive sensitization and impairs spinally mediated learning. In contrast, relational learning induces a form of adaptive plasticity that counters these adverse effects. SCI sets the stage for nociceptive sensitization by disrupting serotonergic (5HT) fibers that quell overexcitation. The loss of 5HT can enhance neural excitability by reducing membrane-bound K-Cl cotransporter 2, a cotransporter that regulates the outward flow of Cl. This increases the intracellular concentration of Cl, which reduces the hyperpolarizing (inhibitory) effect of gamma-aminobutyric acid. Uncontrollable noxious stimulation also undermines the recovery of locomotor function, and increases behavioral signs of chronic pain, after a contusion injury. Nociceptive stimulation has a greater effect if experienced soon after SCI. This adverse effect has been linked to a downregulation in brain-derived neurotrophic factor and an upregulation in the cytokine, tumor necrosis factor. Noxious input enhances tissue loss at the site of injury by increasing the extent of hemorrhage and apoptotic/pyroptotic cell death. Intrathecal lidocaine blocks nociception-induced hemorrhage, cellular indices of cell death, and its adverse effect on behavioral recovery. Clinical implications are discussed.

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

“…Because hemoglobin is cytotoxic (Regan and Guo, 1998 ), this would fuel cell death and the expansion of injury. We have related these effects to the up-regulation of Sur1-Trpm4 channel (Grau et al, 2017 ), which can fuel the loss of endothelial cells and lead to capillary fragmentation through a process known as progressive hemorrhagic necrosis (Simard et al, 2007 , 2012 ).…”

“…Prior work has shown that noxious stimulation can impact spinal cord function and undermine neural plasticity (Grau et al, 1998 ; Crown et al, 2002 ; Joynes et al, 2003 ; reviewed in Grau et al, 2006 , 2012 , 2017 ). These findings emerged from studies examining whether neurons caudal to a complete spinal cord transection could support learning (Grau et al, 1998 ; Grau, 2014 ; Joynes and Grau, 2004 ).…”

Increased Levels of Circulating Glial Fibrillary Acidic Protein and Collapsin Response Mediator Protein-2 Autoantibodies in the Acute Stage of Spinal Cord Injury Predict the Subsequent Development of Neuropathic Pain

“…For instance, damage to nociceptive primary afferents, chronic disruption of the blood-spinal cord barrier, and enhanced excitability of nociceptors have all been proposed as potential mechanisms. [11][12][13][14][15] Although these studies are beginning to provide a cellular and molecular basis for neuropathic pain, there is currently no distinguishing characteristic or biomarker available to identify SCI patients that are at elevated risk for developing this condition.…”

Stretching adversely modulates locomotor capacity following spinal cord injury via activation of nociceptive afferents.

“…Finally, what are the physiological mechanisms underlying the stretchinduced locomotor deficits? Based on the existing literature and specifically work by Grau et al, [172] we first, wanted to investigate the role of nociceptive afferents in mediating the negative effects of stretching on locomotor function. Therefore, the goal of the following thesis is to answer the questions stated above.…”

“…While the first observation could be explained by a complex modulatory effect of nociceptive afferents on locomotor circuitry through the flexor reflex afferent pathway [241], the latter effect might be the result of maladaptive plasticity resulting from "uncontrollable" nociceptive signaling in the already vulnerable post-injury spinal cord exhibiting a compromised inhibitory system [172]. While the clinical relevance of the stretching phenomenon still needs to be established, these findings nonetheless have significant implications for rehabilitation after SCI.…”