Endoplasmic reticulum stress: The underlying mechanism of chronic pain

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.