BDNF Driven Coupling Between KCC2 Downregulation and Fyn-Dependent Phosphorylation of GluN2B NMDA Receptors in Human Spinal Pain Processing

Hyperexcitation of neurons in the dorsal horn of the spinal cord leads to chronic pain. In rodent pain models, the neurotrophic factor BDNF mediates loss of inhibitory signalling. This permits enhancement of excitatory GluN2B-NMDAR currents in lamina I neuronal synapses. However, whether this pathway is conserved between rodents and humans as well as between sexes is unknown. We developed a humanex vivoBDNF model of pathological pain using postmortem human spinal tissue. We found thatex vivoBDNF downregulates KCC2 and active STEP61 and upregulates active Fyn and phosphorylated GluN2B at the superficial dorsal horn in both human and rodent males. We also show that BDNF increases intracellular KCC2 of superficial dorsal horn neurons. Thus, our human model may connect the vast translational divide between rodent and human chronic pain mechanisms to identify and validate new therapeutic targets for human chronic pain.