LRP1/AMPK/mTORC1 signaling in Large-Diameter Sensory Neurons Is Essential for TAFA4 Analgesia

Pain, whether acute or persistent, represents a major global medical challenge. Despite decades of research, current analgesic strategies remain largely unsatisfactory, in part because most therapies repeatedly target the same receptors or ion channels involved in inflammation or central nervous system activity. Here, we identify a distinct peripheral pathway that directly modulates a defined subset of sensory neurons to relieve pain. We show that the secreted protein TAFA4 exerts analgesic effects by signaling through the Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) in large-diameter sensory neurons. This signaling activates AMPK, which in turn inhibits mTORC1, a key driver of neuronal sensitization. Pharmacological blockade of AMPK or forced activation of mTORC1 abolishes TAFA4-induced analgesia, confirming the central role of the LRP1/AMPK/mTORC1 axis. Our findings reveal a previously unrecognized sensory neuron pathway that mediates pain relief and highlight a promising molecular target for the development of peripheral analgesics.