Agenda

The global opiate crisis has highlighted how unsatisfactory current pain treatments are. Our team has recently shown that the neuropeptide TAFA4, which is enriched in a subpopulation of sensory neurons named C-LTMRs (C-Low Threshold MechanoReceptors), can transiently abolish the mechanical hypersensitivity induced by various pain models in mice. The aim of my thesis was to determine the mode of action of TAFA4 at the cellular and molecular levels. We showed that LRP1 in sensory neurons is necessary and sufficient for the peripheral painkilling effect of TAFA4. We further demonstrated that TAFA4-mediated painkilling effect occurs through LRP1 in Aβ-LTMR. Using immunoprecipitation experiments, we have also shown that TAFA4 interacts with a wide range of proteins, many of which belong to phosphatase proteins. This interaction has real biological relevance since TAFA4 modulates the phosphatase activity of sensory neurons in culture. Specifically, we have shown that TAFA4 reduces mTORC1 phosphorylation, identifying a role of the TAFA4/LRP1/mTOR axis in pain modulation. In addition, we also investigated the involvement of LRP1 in sensory neurons on pain pathways. We showed that loss of LRP1 in A-fibers results in both mechanical hypersensitivity to light touch under naive conditions, and prolonged hypersensitivity after paw incision. In contrast, selective ablation of LRP1 in CGRP-expressing neurons results in long-term hypersensitivity following inflammation.Collectively, my work demonstrates that the peripheral painkilling effect of TAFA4 occurs through modulation of Aβ-LTMRs activity, making it a potent disease-modifying molecule for the treatment of injury-induced pain with minimal central nervous system’s side effects.