Unidirectional Crosstalk Between NTRK1 and IGF2 Drives ER Stress in Chronic Pain.

: Chronic postsurgical pain (CPSP) poses a major clinical challenge due to unresolved links between neurotrophic pathways and endoplasmic reticulum (ER) stress. While Neurotrophic Tyrosine Kinase Receptor Type 1 (NTRK1) modulates ER stress in neuropathic pain, its interaction with Insulin-Like Growth Factor II (IGF2) in CPSP remains uncharacterized, impeding targeted therapy. This study defined the spinal NTRK1-IGF2-ER stress axis in CPSP. : Using a skin/muscle incision-retraction (SMIR) rat model, we integrated molecular analyses and intrathecal targeting of NTRK1 (GW441756) or IGF2 (siRNA). SMIR surgery upregulated spinal NTRK1, IGF2, and ER stress mediators. NTRK1 inhibition reduced both NTRK1/IGF2 expression and ER stress, reversing mechanical allodynia. IGF2 silencing attenuated ER stress and pain but did not affect NTRK1, revealing a unidirectional signaling cascade where NTRK1 drives IGF2-dependent ER stress amplification. These findings expand understanding of stress-response networks in chronic pain. : We show that spinal NTRK1 drives IGF2-mediated ER stress to sustain CPSP. The NTRK1-IGF2-ER stress axis represents a novel therapeutic target; NTRK1 inhibitors and IGF2 biologics offer non-opioid strategies for precision analgesia. This work advances CPSP management and demonstrates how decoding unidirectional signaling hierarchies can transform neurological disorder interventions.