Regulation of NMDA Receptor Subtypes in Pain Processing Neurons within Lamina I of the Spinal Cord

In lamina I (LI) of the spinal cord dorsal horn, excitatory NMDARs containing GluN2B subunits are phosphorylated and potentiated by Src family kinase (SFK) through BDNF signalling in chronic pain models. Contributions of GluN2B to synaptic responses in the brain makes it a difficult target to specifically treat pain. This study tested whether GluN2D-containing NMDARs are necessary for BDNF-mediated potentiation of NMDARs, whether GluN2D-containing NMDARs are functionally present at juvenile LI synapses and whether SFKs potentiate these receptors. Pharmacological inhibition of either GluN2D or GluN2B prevented potentiation by BDNF in adult spinal cord slices. Inhibition of GluN2A- and GluN2B-containing NMDARs resulted in residual charge transfer through NMDARs, attributed to GluN2D-containing NMDARs. When GluN2B/D-containing NMDARs were pharmacologically isolated, SFK activation failed to potentiate either isolated receptor subtype. We propose that LI of the dorsal horn may contain triheteromeric GluN2B/D NMDARs which do not undergo potentiation in the presence of GluN2B/D antagonists.