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J. Adv. Res., Mar 05 2025, S2090-1232(25)00146-8 | https://doi.org/10.1016/j.jare.2025.03.005
The LRP1-SHP2 pathway regulates TRPV1 sensitivity in the peripheral nervous system: Insights from amyloid beta 1-42 modulation
Sung-Min Hwang a,1, Jueun Roh a,1, Eun Jin Go a,1, Jing-Ying Pan b, Jaeik Park a, Mahbubur Rahman a, YunJae Jung c, Sun-Ho Lee d, Inbo Han e, Gehoon Chung f, Sang Hoon Lee g, Temugin Berta g, Chul-Kyu Park a,c, Yong Ho Kim a,c
aGachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea
bDepartment of Histology and Embryology, Medical School of Nantong University, Nantong, Jiangsu Province 226001, China
cDepartment of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea
dDepartment of Neurosurgery, Spine Tumor Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
eDepartment of Neurosurgery, School of Medicine, CHA University, CHA Bundang Medical Center, Seongnam-si 13496, Republic of Korea
fDepartment of Oral Physiology, School of Dentistry, Seoul National University, Seoul 08826, Republic of Korea
gPain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH, USA
1These authors contributed equally to this work.
Corresponding authors : Chul-Kyu Park, Yong Ho Kim
aGachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea
bDepartment of Histology and Embryology, Medical School of Nantong University, Nantong, Jiangsu Province 226001, China
cDepartment of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea
dDepartment of Neurosurgery, Spine Tumor Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
eDepartment of Neurosurgery, School of Medicine, CHA University, CHA Bundang Medical Center, Seongnam-si 13496, Republic of Korea
fDepartment of Oral Physiology, School of Dentistry, Seoul National University, Seoul 08826, Republic of Korea
gPain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH, USA
1These authors contributed equally to this work.
Corresponding authors : Chul-Kyu Park, Yong Ho Kim
Abstract
Introduction: Mature adults often exhibit higher pain thresholds than younger individuals. However, this phenomenon is poorly understood, especially with regards to peripheral nervous system signaling.
Objectives: We investigated the involvement of amyloid beta (Aβ) in regulating heat pain sensitivity within the dorsal root ganglion (DRG) during adult maturation.
Methods: We employed various in vivo and in vitro techniques to investigate the modulatory effect of Aβ1-42. Heat pain sensitivity alteration was examined in spared nerve injury (SNI) models of young and mature adult Aβ1-42-treated mice. Phosphorylation and receptor inhibition assays were performed to elucidate the molecular mechanisms involved in pathway interactions in vitro.
Results: Mature adult mice had higher thermal pain thresholds and elevated levels of Aβ1-42 compared to younger mice. In vitro analyses indicated that Aβ1-42-induced activation of low-density lipoprotein receptor-related protein 1 (LRP1) led to phosphorylation of the src-homology domain-2-containing protein tyrosine phosphatase 2 (SHP2), which in turn inhibited transient receptor potential vanilloid 1 (TRPV1) function in primary DRG neurons. Similar mechanisms were observed in Aβ1-42-treated human DRG neurons. Additionally, α2-macroglobulin (α2M), a potent LRP1 agonist, also inhibited TRPV1 activity and reduced heat pain sensitivity through the LRP1-SHP2 pathway. In vivo studies with the mouse SNI model demonstrated that intraplantar injection of Aβ1-42 and α2M enhanced the paw withdrawal latency; these effects were reversed by low-density lipoprotein receptor-related protein-associated protein 1.
Conclusion: The findings suggest a crucial role of Aβ in modulating heat pain sensitivity during maturation through TRPV1 inhibition. The study offers new insights into the regulation of pain sensitivity during the maturation process by revealing a novel intrinsic mechanism involving Aβ1-42 in heat pain sensitivity and its regulation through the LRP1/SHP2 pathway in mature adults. This pathway could be a potential therapeutic target for age-related chronic pain management.
Objectives: We investigated the involvement of amyloid beta (Aβ) in regulating heat pain sensitivity within the dorsal root ganglion (DRG) during adult maturation.
Methods: We employed various in vivo and in vitro techniques to investigate the modulatory effect of Aβ1-42. Heat pain sensitivity alteration was examined in spared nerve injury (SNI) models of young and mature adult Aβ1-42-treated mice. Phosphorylation and receptor inhibition assays were performed to elucidate the molecular mechanisms involved in pathway interactions in vitro.
Results: Mature adult mice had higher thermal pain thresholds and elevated levels of Aβ1-42 compared to younger mice. In vitro analyses indicated that Aβ1-42-induced activation of low-density lipoprotein receptor-related protein 1 (LRP1) led to phosphorylation of the src-homology domain-2-containing protein tyrosine phosphatase 2 (SHP2), which in turn inhibited transient receptor potential vanilloid 1 (TRPV1) function in primary DRG neurons. Similar mechanisms were observed in Aβ1-42-treated human DRG neurons. Additionally, α2-macroglobulin (α2M), a potent LRP1 agonist, also inhibited TRPV1 activity and reduced heat pain sensitivity through the LRP1-SHP2 pathway. In vivo studies with the mouse SNI model demonstrated that intraplantar injection of Aβ1-42 and α2M enhanced the paw withdrawal latency; these effects were reversed by low-density lipoprotein receptor-related protein-associated protein 1.
Conclusion: The findings suggest a crucial role of Aβ in modulating heat pain sensitivity during maturation through TRPV1 inhibition. The study offers new insights into the regulation of pain sensitivity during the maturation process by revealing a novel intrinsic mechanism involving Aβ1-42 in heat pain sensitivity and its regulation through the LRP1/SHP2 pathway in mature adults. This pathway could be a potential therapeutic target for age-related chronic pain management.
논문정보
- Research article
- 2025년 03월 (BRIC 등록일 2025-03-10)
- 국내(교신)+국외 연구진
- 의약학 > 신경의학
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