Effects of D-Serine and MK-801 on Neuropathic Pain and Functional Recovery in a Rat Model of Spinal Cord Injury

OBJECTIVE: Neuropathic pain is a common secondary complication of spinal cord injury (SCI). N-methyl-D-aspartate (NMDA) receptor activation is critical for hypersensitivity in neuropathic pain. This activation requires the binding of both glutamate and the D-serine co-agonist to the NMDA glycine site. We evaluated the effects of D-serine on neuropathic pain after SCI and explored the underlying molecular mechanisms. METHODS: Anesthetized rats underwent T9 spinal cord contusion (130 kdyn). D-serine (500 and 1,000 mg/kg) and MK-801 hydrogen maleate (2.0 mg/kg) were injected daily for 2 weeks, starting the day after SCI. Functional outcomes were assessed according to the Basso, Beattie, and Bresnahan scale, while histological outcomes were evaluated based on lesion volume and spared tissue area. Mechanical allodynia and thermal hyperalgesia were evaluated by measuring the withdrawal threshold of a von Frey filament and hot/cold plate latency. Western blotting was performed to determine the expression levels of Trpv1, Nav1.9, calcitonin gene-related peptide (CGRP), and β-actin in damaged tissue. RESULTS: The withdrawal threshold values and latency of the D-serine group were significantly lower than those of the noninjection group. The MK-801 group showed higher threshold values and latencies than the other groups. Western blotting showed increased Nav1.9 and Trpv1 levels and lower CGRP levels in the D-serine group, whereas the MK-801 group showed the opposite results. CONCLUSION: D-serine increases neuropathic pain after traumatic SCI by mediating the NMDA receptor. NMDA receptor antagonists alleviate neuropathic pain after traumatic SCI.