Khalid N, Shafin N, Long I, Hasim H, Ismail CAN. Targeting N-methyl-D-aspartate 2B receptor in painful diabetic neuropathy – mechanisms, challenges, and emerging therapeutics. World J Diabetes 2026; 17(1): 110108 [DOI: 10.4239/wjd.v17.i1.110108]
Corresponding Author of This Article
Che Aishah Nazariah Ismail, PhD, Lecturer, Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian 16150, Kelantan, Malaysia. aishahnazariah@usm.my
Research Domain of This Article
Neurosciences
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Minireviews
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Jan 15, 2026 (publication date) through Jan 14, 2026
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Journal Information of This Article
Publication Name
World Journal of Diabetes
ISSN
1948-9358
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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
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Khalid N, Shafin N, Long I, Hasim H, Ismail CAN. Targeting N-methyl-D-aspartate 2B receptor in painful diabetic neuropathy – mechanisms, challenges, and emerging therapeutics. World J Diabetes 2026; 17(1): 110108 [DOI: 10.4239/wjd.v17.i1.110108]
Nayab Khalid, Department of Physiology, Islam Medical College, Sialkot City 51040, Punjab, Pakistan
Nazlahshaniza Shafin, Che Aishah Nazariah Ismail, Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian 16150, Kelantan, Malaysial
Idris Long, Department of Biomedicine, School of Health Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian, Kota Bharu 16150, Kelantan, Malaysia
Hidani Hasim, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Bertam 13200, Pulau Pinang, Malaysia
Author contributions: Khalid N and Ismail CAN contributed written ideas and insights, conceptualized and prepared the manuscript; Shafin N, Hasim H, and Long I proofread the manuscript.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Che Aishah Nazariah Ismail, PhD, Lecturer, Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian 16150, Kelantan, Malaysia. aishahnazariah@usm.my
Received: May 29, 2025 Revised: July 31, 2025 Accepted: December 2, 2025 Published online: January 15, 2026 Processing time: 230 Days and 9.4 Hours
Abstract
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.
Core Tip: The N-methyl-D-aspartate receptor 2B (NMDAR-2B) plays a pivotal role in the pathophysiology of painful diabetic neuropathy (DN). In this review, the contribution of NMDAR-2B to oxidative stress, neuroinflammation, and central sensitisation was underscored. Experimental and clinical data linking NMDAR-2B upregulation with chronic pain were also discussed. Furthermore, emerging therapeutics targeting the receptor were evaluated, while outlining the translational challenges. Comprehending the molecular interplay of NMDAR-2B with glial cells and signalling pathways might also provide valuable insight for developing multi-targeted or precision-based therapies to improve painful DN management.
