TRPM2 is a direct pain transducer

• 成果类型: Article
• 署名作者: Varghese, Linda; Alizada, Mujahid; Yang, Jinquan; Feng, Ye; Yuan, Xiaoqiu; Malhotra, Mitali; Zhang, Xuming
• 署名单位: University of Warwick
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2532289123
• 发表日期: 2026-09-22
• 页码: e2532289123
• 关键词: pain; trp channels; PGE2; autoantibody; DRG; IGG IMMUNE-COMPLEX; ROOT GANGLION NEURONS; necrosis-factor-alpha; GAMMA RECEPTOR-I; oxidative stress; adp-ribose; neuropathic pain; ion-channel; activation; inflammation

摘要

Chronic pain results from maladaptive interaction between the immune and nervous systems. TRPM2 channels in immune cells (immune TRPM2) are believed to facilitate chronic pain by indirectly promoting immune-inflammatory responses, whereas TRPM2 in sensory neurons (neuronal TRPM2) acts as a warmth sensor critical to sense innocuous warm temperatures. However, neuronal TRPM2 mediates the warmth sensitivity of less than 3.5% of sensory neurons. The functions of the vast majority of TRPM2+ neurons are unknown. Here, we show that neuronal TRPM2 functions as a pain sensor responsible for directly transducing acute and chronic pain independently of immune TRPM2. Both chronic arthritis pain and neuropathic pain were markedly reduced in TRPM2-knockout mice, and the pain deficit was recapitulated by sole deletion of neuronal TRPM2. However, immune and inflammatory responses were largely similar between wild-type and neuronal TRPM2-deficient mice. Moreover, antagonizing TRPM2 rapidly reversed arthritis pain and neuropathic pain. Notably, TRPM2 is activated by PGE2 and IgG immune complex (IgG-IC) through coupling to G alpha oA and Fc gamma RI, respectively, independently of conventional signaling messengers. Consistently, acute pain induced by PGE2 and IgG-IC was abolished in TRPM2 mutant mice. We conclude that neuronal TRPM2 is a convergent direct pain transducer independently of inflammation, representing an appealing target for alleviating chronic pain.