Schwann cell p75NTR sustains persistent pain downstream to NGF through ROS-dependent TRPA1 signaling

<jats:p>Nerve growth factor (NGF) is a key mediator of pain through activation of the high-affinity tropomyosin receptor kinase A (TrkA) and the low-affinity neurotrophin receptor (p75NTR). Although neuronal TrkA signaling is well established, the contribution of non-neuronal cells to NGF-dependent pain remains unclear. Here, we show that NGF and its precursor proNGF engage distinct cellular mechanisms. Intraplantar NGF induced acute nociception, heat hyperalgesia, mechanical allodynia, and cold hypersensitivity, whereas cleavage-resistant proNGF selectively evoked mechanical allodynia and cold hypersensitivity. Pharmacological and cell-specific genetic approaches demonstrated that acute nociception and heat hyperalgesia require neuronal TrkA, whereas mechanical and cold hypersensitivity depend on p75NTR activation in Schwann cells. In Schwann cells, NGF and proNGF induced p75NTR-dependent calcium release, followed by TRPA1 activation, mitochondrial ROS production, and NOX1-dependent oxidative amplification. Inhibition of ROS or TRPA1, or Schwann cell-specific Trpa1 deletion, markedly reduced mechanical allodynia and cold hypersensitivity without affecting acute nociception or heat hyperalgesia. These findings identify a Schwann cell p75NTR-ROS-TRPA1 pathway sustaining persistent pain and highlight non-neuronal p75NTR signaling as a potential therapeutic target.</jats:p>