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

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

<b>Background</b>: 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 intera...

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Bibliographic Details
Main Authors: Caixia Zhang, Kaiwen Zhang, Wencui Zhang, Bo Jiao, Xueqin Cao, Shangchen Yu, Mi Zhang, Xianwei Zhang
Format: Article
Language:English
Published: MDPI AG 2025-07-01
Series:Biomedicines
Subjects:
Neurotrophic Tyrosine Kinase Receptor Type 1
Insulin-Like Growth Factor II
Endoplasmic reticulum stress
Chronic Post-surgical Pain
Online Access:https://www.mdpi.com/2227-9059/13/7/1632
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Summary:<b>Background</b>: 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. <b>Methods</b>: Using a skin/muscle incision–retraction (SMIR) rat model, we integrated molecular analyses and intrathecal targeting of NTRK1 (GW441756) or IGF2 (siRNA). <b>Results:</b> 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. <b>Conclusions</b>: 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.
ISSN:2227-9059

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