Dissecting signaling pathways in inflammatory pain through protein-protein interaction modulation to identify new therapeutic strategies

Exploring protein-protein interactions in nociceptors is a promising strategy to develop new analgesics. With this in mind, we identified nonsense mutations found in patients with Congenital Insensitivity to Pain (CIPA), occurring within the last exon of NTRK1. These mutations produce truncated Tropomyosin receptor kinase A (TrkA), disrupting its interaction with phospholipase Cγ (PLC γ) and hence, lipase activation, underscoring the importance of this interaction in pain signaling. A rationally designed peptide (TAT-pQYP) mimicking TrkA’s binding site to PLC γ’s SH2 domain, prevented lipase phosphorylation/activation and decreased inflammatory mechanical hypernociception caused by Complete Freund’s Adjuvant (CFA). In a capsaicin-induced neurogenic inflammation model induced, a decrease in edema by disrupting vascular endothelial growth factor A (VEGFA)/endothelial nitric oxide synthase (eNOS) signaling, and reversed mechanical hypernociception by disrupting NGF/transient receptor potential vanilloid 1 (TRPV1) signaling, although no effect was found on chemonociception or neuropeptide release, important for NGF/ VEGFA secretion by mastocytes. Altogether, our results show that specifically targeting key protein-protein interactions mediated by PLCγ and receptors tyrosine kinase, both in endothelial cells and nociceptors, may be a therapeutic strategy that mitigates PLCγ-dependent functions mediated by both NGF and VEGFA, while preserving TRPV1´s physiological activity. From a translational point of view, mRNA expression for PLCγ in human nociceptors is concentrated in neurons that co-express TrkA and TRPV1, demonstrating the feasibility of targeting this signaling pathway to mitigate pain and modulate neurogenic inflammation. All animal protocols were previously approved by the competent ethics committee of the Institute of Biomedical Sciences of the university of São Paulo (CEUA CEUA, 7474280219 and 4121050423). This study was financed by the São Paulo research foundation (FAPESP) 2019/06982-6. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.