EXPRESS: "One coin, two aspects": The role of IGF1R singling in chronic pain.

Abstract

Chronic pain, encompasses neuropathic and inflammatory pain, is a major public health burden. The insulin-like growth factor 1 receptor (IGF1R) has emerged as a critical player in pain modulation, exhibiting dual roles in both pain promotion and resolution. Recent studies have identified Follistatin (FST) as a novel ligand for IGF1R in neuropathic pain, where it activates the ERK/AKT signaling pathway, enhances Nav1.7-mediated sodium channel function, and induces neuronal hyperexcitability. Targeting the FST-IGF1R interaction with antagonist peptides has shown promise in alleviating neuropathic pain, highlighting its therapeutic potential. Conversely, IGF1/IGF1R signaling has also been implicated in pain resolution, particularly through CD11c+ microglia in the spinal dorsal horn, which promote recovery from neuropathic pain by phagocytosing myelin debris and modulating inflammatory responses. These findings underscore the context-dependent nature of IGF1R signaling, which can drive both nociceptive hypersensitivity and pain relief. This work synthesizes recent advances in understanding the multifaceted roles of IGF1R in chronic pain, offering novel insights into its mechanisms and therapeutic applications, and paving the way for the development of targeted therapies to address the complex challenges of chronic pain management.