Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Neurobiol Dis. 2024 Nov;202:106697. doi: 10.1016/j.nbd.2024.106697. Epub 2024 Oct 9.
Chronic pain (CP) affects over 30 % of the global population, imposing significant financial burdens on individuals and society. However, existing treatments for CP offer limited efficacy and troublesome side effects, primarily owing to a lack of knowledge of its precise underlying mechanism. Pathological stimuli disrupt the intricate process of protein folding and endoplasmic reticulum (ER) homeostasis. This disruption leads to the accumulation of misfolded or unfolded proteins in the ER, generating a condition termed ER stress. Emerging data have indicated that ER stress, occurring in the peripheral and central nervous systems, contributes to the development and maintenance of CP. This review aimed to comprehensively explore the intersection of ER stress and CP within the lower and upper nervous systems and highlight the cell-specific contributions of the unfolded protein response in different CP types. We provide a comprehensive synthesis of evidence from animal models, examining neuronal and non-neuronal mechanisms and discuss the damaging ER stress-linked inflammation, autophagy, oxidative stress, and apoptosis, which collectively drive disease progression and contribute to a neurotoxic environment. However, the mechanisms through which ER stress influences the most advanced centre-of-pain projections in the brain remain unclear. Further investigation in this area is crucial to elucidate the relationship between ER stress and CP and facilitate the development of novel therapeutic drugs for this intractable dilemma.
慢性疼痛（CP）影响了全球超过 30%的人口，给个人和社会带来了巨大的经济负担。然而，现有的 CP 治疗方法疗效有限，且存在副作用问题，这主要是因为我们对其确切的潜在机制缺乏了解。病理性刺激破坏了蛋白质折叠和内质网（ER）稳态的复杂过程。这种破坏导致 ER 中错误折叠或未折叠的蛋白质积累，产生一种称为 ER 应激的情况。新出现的数据表明，ER 应激发生在周围和中枢神经系统中，导致 CP 的发展和维持。本综述旨在全面探讨 ER 应激与 CP 在上下神经系统中的交叉点，并强调未折叠蛋白反应在不同 CP 类型中的细胞特异性贡献。我们从动物模型中提供了全面的综合证据，检查神经元和非神经元机制，并讨论了与疾病进展相关的破坏性 ER 应激相关炎症、自噬、氧化应激和细胞凋亡，这些共同导致了神经毒性环境。然而，ER 应激影响大脑中疼痛中心投射的最先进机制仍不清楚。在这一领域进行进一步的研究对于阐明 ER 应激与 CP 之间的关系以及为这一棘手问题开发新的治疗药物至关重要。
