Analgesia Induced by Spinal Cord Stimulation Following Spinal Cord Injury Associated with The Activation of Neuroral Progenitor Cells

Abstract

Introduction: Spinal cord stimulation has been shown to be effective in the management of peripheral neuropathic pain 1-2, although its effects on central neuropathic pain are largely unknown. Materials/Methods: Adult male Sprague-Dawley rats were implanted with monopolar electrodes at the time of spinal cord injury (unilateral dorsal quadrant lesion). Dorsal columns at spinal segment T12 were stimulated 3 days later (earlyspinal cord stimulation), and again at day 7 (late-spinal cord stimulation) using low frequency parameters. Hypersensitivity to cutaneous mechanical stimuli was assessed using von Frey filaments. Lumbar spinal cords were collected after perfusion and cryosectioned for immunofluorescence staining with antibodies against the neural progenitor cell marker nestin and the GABAergic neuron marker, parvalbumin. Results: Behavioural tests showed that early-spinal cord stimulation caused partial reversal of mechanical hypersensitivity caused by spinal cord injury and this reversal was amplified by late-spinal cord stimulation, compared to spinal cord-injured animals without spinal cord stimulation. Immunochemical assessment revealed that nestin-immunoreactive cells could be identified in the ipsilateral superficial dorsal horn after spinal cord stimulation in spinal cord-injured rats, ranging over some 600 mm rostral from the lesion with an estimated number of 400-500 cells in total. In contrast, nestin-positive cells were rarely observed in superficial dorsal horn of naïve or unstimulated spinal cord-injured rats (with total counts of around 20 cells and 40 cells, respectively). Around 48% of the nestin-positive cells were co-stained with the GABAergic neuron marker, parvalbumin. Discussion: We firstly found that spinal cord stimulation can alleviate mechanical allodynia caused by spinal cord injury, and repetitive spinal cord stimulation provided a long-lasting and incremental anti-hyperalgesic effect. Moreover, our study indicates that the central mechanism of the spinal cord stimulation-induced antinociception after spinal cord injury might be associated with the increased neural progenitor cell as many of them additionally showed some characteristics of GABA neurons. Conclusions: A long-lasting and incremental reversal of hyperalgesia can be achieved, through activation of the spinal neuronal progenitors, by repetitive spinal cord stimulation in a central neuropathic pain model.