The LRP1-SHP2 pathway regulates TRPV1 sensitivity in the peripheral nervous system: Insights from amyloid beta 1-42 modulation.

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 Aβ(1-42). Heat pain sensitivity alteration was examined in spared nerve injury (SNI) models of young and mature adult Aβ(1-42)-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 Aβ(1-42) compared to younger mice. In vitro analyses indicated that Aβ(1-42)-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 Aβ(1-42)-treated human DRG neurons. Additionally, α(2)-macroglobulin (α(2)M), 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(1-42) and α(2)M 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 Aβ(1-42) 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.