Hwang Sung-Min, Roh Jueun, Go Eun Jin, Pan Jing-Ying, Park Jaeik, Rahman Mahbubur, Jung YunJae, Lee Sun-Ho, Han Inbo, Chung Gehoon, Lee Sang Hoon, Berta Temugin, Park Chul-Kyu, Kim Yong Ho
Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea.
Department of Histology and Embryology, Medical School of Nantong University, Nantong, Jiangsu Province 226001, China.
J Adv Res. 2026 Jan;79:461-474. doi: 10.1016/j.jare.2025.03.005. Epub 2025 Mar 5.
Mature adults often exhibit higher pain thresholds than younger individuals. However, this phenomenon is poorly understood, especially with regards to peripheral nervous system signaling.
We investigated the involvement of amyloid beta (Aβ) in regulating heat pain sensitivity within the dorsal root ganglion (DRG) during adult maturation.
We employed various in vivo and in vitro techniques to investigate the modulatory effect of Aβ. Heat pain sensitivity alteration was examined in spared nerve injury (SNI) models of young and mature adult Aβ-treated mice. Phosphorylation and receptor inhibition assays were performed to elucidate the molecular mechanisms involved in pathway interactions in vitro.
Mature adult mice had higher thermal pain thresholds and elevated levels of Aβ compared to younger mice. In vitro analyses indicated that Aβ-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 Aβ-treated human DRG neurons. Additionally, α-macroglobulin (αM), 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 Aβ and αM enhanced the paw withdrawal latency; these effects were reversed by low-density lipoprotein receptor-related protein-associated protein 1.
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 Aβ 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.
成熟成年人的痛阈通常高于年轻人。然而，这一现象尚未得到充分理解，尤其是在外周神经系统信号传导方面。
我们研究了β淀粉样蛋白（Aβ）在成年期成熟过程中对背根神经节（DRG）内热痛敏感性调节的作用。
我们采用了多种体内和体外技术来研究Aβ的调节作用。在年轻和成熟成年Aβ处理小鼠的 spared 神经损伤（SNI）模型中检测热痛敏感性变化。进行磷酸化和受体抑制试验以阐明体外途径相互作用中涉及的分子机制。
与年轻小鼠相比，成熟成年小鼠具有更高的热痛阈和更高水平的Aβ。体外分析表明，Aβ诱导的低密度脂蛋白受体相关蛋白1（LRP1）激活导致含src同源结构域2的蛋白酪氨酸磷酸酶2（SHP2）磷酸化，进而抑制初级DRG神经元中的瞬时受体电位香草酸受体1（TRPV1）功能。在Aβ处理的人DRG神经元中也观察到类似机制。此外，α巨球蛋白（αM），一种有效的LRP1激动剂，也通过LRP1-SHP2途径抑制TRPV1活性并降低热痛敏感性。小鼠SNI模型的体内研究表明，足底注射Aβ和αM可延长爪退缩潜伏期；这些作用可被低密度脂蛋白受体相关蛋白相关蛋白1逆转。
研究结果表明Aβ在成熟过程中通过抑制TRPV1调节热痛敏感性方面起关键作用。该研究通过揭示成熟成年人中涉及Aβ的热痛敏感性及其通过LRP1/SHP2途径调节的新内在机制，为成熟过程中痛觉敏感性的调节提供了新见解。该途径可能是与年龄相关的慢性疼痛管理的潜在治疗靶点。
