D-Aspartate Modulates Nociceptive-Specific Neuron Activity and Pain Threshold in Inflammatory and Neuropathic Pain Condition in Mice

Abstract

D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist on NMDA receptors (NMDARs). Accordingly, high levels of D-Asp in knockout mice forDdogene (Ddo−/−) or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated inDdo−/−mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found thatDdo−/−mice show an increased evoked activity of the nociceptive specific (NS) neurons of the dorsal horn of the spinal cord (L4–L6) and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover,Ddogene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions.