Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: Role of tumor necrosis factor alpha and apoptosis

Abstract

We previously showed that peripheral noxious input after spinal cord injury (SCI) inhibits beneficial spinal plasticity and impairs recovery of locomotor and bladder functions. These observations suggest that noxious input may similarly affect the development and maintenance of chronic neuropathic pain, an important consequence of SCI. In adult rats with a moderate contusion SCI, we investigated the effect of noxious tail stimulation, administered one day after SCI, on mechanical withdrawal responses to von Frey stimuli from 1 to 28 days, post-treatment. In addition, because the pro-inflammatory cytokine tumor necrosis factor α (TNFα) is implicated in numerous injury-induced processes including pain hypersensitivity, we assessed the temporal and spatial expression of TNFα, TNF receptors, and several downstream signaling targets after stimulation. Our results showed that unlike sham surgery or SCI only, nociceptive stimulation following SCI induced mechanical sensitivity by 24 hours. These behavioral changes were accompanied by increased expression of TNFα. Cellular assessments of downstream targets of TNFα revealed that nociceptive stimulation increased the expression of caspase 8 and the active subunit (12 kDa) of caspase 3 at a time point consistent with the onset of mechanical allodynia, indicative of active apoptosis. In addition, immunohistochemical analysis revealed distinct morphological signs of apoptosis in neurons and microglia at 24 hours post-stimulation. Interestingly, expression of the inflammatory mediator NFκB was unaltered by nociceptive stimulation. These results suggest that noxious input caudal to the level of SCI can increase the onset and expression of behavioral responses indicative of pain, potentially involving TNFα signaling.

Neurobiological Effects of Morphine after Spinal Cord Injury

“…[5][6][7][8]30 Despite the loss of neurons, however, repeated morphine administration led to the development of opioid-induced hyperalgesia, with subjects displaying increased reactivity to innocuous mechanical stimulation. As suggested by Garraway and associates, 29 a loss of GABAergic neurons after SCI, and morphine in the current study, may underlie this paradoxical pain hypersensitivity. The dramatic effects of morphine on NeuN and GFAP expression are commensurate with data from other models demonstrating apoptosis with morphine administration.…”

“…21,[23][24][25] In addition, proinflammatory cytokines, such as IL-1b and TNFa, have been implicated in neuronal apoptosis after SCI. [26][27][28][29] In sum, opioid administration may synergistically contribute to the pathology of SCI to increase the development of pain and cell death, and decrease functional recovery.…”

Effect of TNF-α Inhibition on Bone Marrow-Derived Mesenchymal Stem Cells in Neurological Function Recovery after Spinal Cord Injury via the Wnt Signaling Pathway in a Rat Model

“…Additionally, TNF-α induces over-expression of matrix metalloprotease 9 (MMP9) in localized cancer, and MMP9 can be reduced via dexmedetomidine preconditioning in rats with ischemia reperfusion injury [25, 26]. The involvement of TNF-α in inflammatory pain is particularly relevant in SCI-induced pain [27]. And the treatment with glycine, a strychnine-sensitive inhibitory neurotransmitter in brainstem, spinal cord and retina, could reduce TNF-α level [28, 29].…”

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

“…Experimental evidence suggests that noxious stimulation undermines the plasticity of the spinal cord, and impairs sensorimotor recovery following SCI. 35,[59][60][61] Clinically, preemptive analgesia has also been used in an effort to prevent the establishment of central sensitization and postoperative pathological pain, [62][63][64] although the effectiveness of this strategy remains controversial.…”