Through a well-established alloxan mediated diabetic model with painful neuropathy, we validated the potential role of memantine on the key cellular and molecular pathways involved in the neuroplasticity in the central nociceptive networks, with special shedding on the spinal neuronal–glial interactions, through targeting the HMGB1/TLR4/NF-kB axis and glutamate synaptic transmission. The gene discussed is HMGB1; the disease is Pain.