Targeting N-methyl-D-aspartate 2B receptor in painful diabetic neuropathy – mechanisms, challenges, and emerging therapeutics

A notable number of patients with diabetes suffer from painful diabetic neuropathy (PDN), which is a debilitating complication of diabetes mellitus. Prolonged hyperglycaemia and metabolic dysregulation lead to PDN, a condition characterised by chronic pain, sensory dysfunction, and reduced quality of life. Although various treatment options are available, clinical management is challenging due to the complex and multifactorial nature of PDN pathophysiology. N-methyl-D-aspartate receptors (NMDARs), particularly the NR2B subtype (NMDAR-2B), have emerged as a key player in the pathophysiology of chronic pain states, including PDN. This review highlights the mechanistic NMDAR-2B involvement in the pathophysiology of PDN, focusing on its upregulation role in pain-processing regions, interaction with inflammatory mediators, glia-derived mediators, and oxidative stress mechanisms. Advancements in targeting NMDAR-2B as a mechanistically driven approach to PDN management also offer potential in enhancing the therapeutic efficacy of NMDAR-2B. Consequently, this review provides a novel perspective on understanding the role of NMDAR-2B in PDN for the future development of effective treatment strategies for managing the condition.