The Role of Peripheral N-Methyl-D-Asparate (NMDA) Receptors in Itch and Pain: A Narrative Review

IF 3.4 2区医学 Q1 ANESTHESIOLOGY

European Journal of Pain Pub Date : 2025-07-21 DOI:10.1002/ejp.70082

Ryusuke Tanaka, Silvia Lo Vecchio, Giulia Erica Aliotta, Lars Arendt-Nielsen

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Abstract

Background and Objective

NMDA receptors, predominantly located in the central nervous system and known for their roles in synaptic plasticity and central sensitisation of pain and itch, are also expressed in peripheral sensory neurons. Emerging evidence suggests that peripheral NMDA receptors contribute to pathological pain and potentially itch, identifying them as promising therapeutic targets. The aim of this review is to explore the role of peripheral NMDA receptors in pain and itch and to summarise the effectiveness of topical NMDA antagonists in managing these sensations.

Databases and Data Treatment

This review was conducted through a systematic search of the PubMed database using MeSH terms and keywords related to ‘peripheral NMDA receptors’, ‘pain’, ‘itch’ and ‘topical ketamine’. Additional references were included based on expert knowledge and reference tracking. Only English-language articles were considered.

Results

Animal studies demonstrate that peripheral NMDA receptors are involved in inflammatory and certain neuropathic pain models, with antagonists showing analgesic effects. Limited studies also suggest their role in non-histaminergic itch through glutamate signalling. In humans, topical ketamine has shown mixed results for pain relief, and preliminary clinical reports suggest potential antipruritic effects. However, controlled clinical trials, particularly for itch, are lacking.

Conclusion

Peripheral NMDA receptors are involved in the transmission and sensitisation of both pain and itch, especially under pathological conditions. While topical ketamine may offer therapeutic benefits, particularly for non-histaminergic itch and neuropathic pain, further clinical research is necessary to confirm its efficacy, safety and optimal use.

Significance Statement

This review highlights the underexplored role of peripheral NMDA receptors in itch, especially non-histaminergic pathways, and synthesises emerging evidence for their therapeutic potential. By comparing pain and itch mechanisms, it suggests that topical ketamine could serve as novel treatments for refractory itch and localised pain, warranting further clinical investigation.

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外周n -甲基- d -天冬氨酸（NMDA）受体在瘙痒和疼痛中的作用：综述

NMDA受体主要存在于中枢神经系统，在突触可塑性和痛痒的中枢致敏中发挥重要作用，也在外周感觉神经元中表达。新出现的证据表明，外周NMDA受体有助于病理疼痛和潜在的瘙痒，确定它们是有希望的治疗靶点。这篇综述的目的是探讨外周NMDA受体在疼痛和瘙痒中的作用，并总结局部NMDA拮抗剂在控制这些感觉方面的有效性。本综述通过对PubMed数据库进行系统搜索，使用MeSH术语和与“外周NMDA受体”、“疼痛”、“瘙痒”和“局部氯胺酮”相关的关键词。基于专家知识和参考文献跟踪，加入了额外的参考文献。只考虑了英文文章。结果动物实验表明，外周NMDA受体参与炎性和某些神经性疼痛模型，拮抗剂具有镇痛作用。有限的研究也表明它们通过谷氨酸信号传导在非组胺性瘙痒中的作用。在人类中，局部氯胺酮在缓解疼痛方面显示出不同的结果，初步临床报告表明可能具有止痒作用。然而，对照临床试验，特别是瘙痒，缺乏。结论外周NMDA受体参与了疼痛和瘙痒的传递和致敏，特别是在病理条件下。虽然局部氯胺酮可能提供治疗效果，特别是对非组胺能性瘙痒和神经性疼痛，但需要进一步的临床研究来确认其有效性、安全性和最佳使用。本综述强调了外周NMDA受体在瘙痒中的作用，特别是非组胺能通路，并综合了其治疗潜力的新证据。通过对疼痛和瘙痒机制的比较，提示局部氯胺酮可作为难治性瘙痒和局部疼痛的新治疗方法，值得进一步的临床研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Pain 医学-临床神经学

CiteScore

7.50

自引率

5.60%

发文量

163

审稿时长

4-8 weeks

期刊介绍： European Journal of Pain (EJP) publishes clinical and basic science research papers relevant to all aspects of pain and its management, including specialties such as anaesthesia, dentistry, neurology and neurosurgery, orthopaedics, palliative care, pharmacology, physiology, psychiatry, psychology and rehabilitation; socio-economic aspects of pain are also covered. Regular sections in the journal are as follows: • Editorials and Commentaries • Position Papers and Guidelines • Reviews • Original Articles • Letters • Bookshelf The journal particularly welcomes clinical trials, which are published on an occasional basis. Research articles are published under the following subject headings: • Neurobiology • Neurology • Experimental Pharmacology • Clinical Pharmacology • Psychology • Behavioural Therapy • Epidemiology • Cancer Pain • Acute Pain • Clinical Trials.