Abstract 1835: The impact of artemin depletion on acute radiation-associated oral pain

Abstract A common complication of therapeutic radiotherapy for head and neck cancer is the development of severe pain. The biological mechanisms underlying acute orofacial radiation-associated pain (RAP) are unknown but may involve cold-sensing and cold-signaling pathways. A key cold receptor is TRPM8 (Transient Receptor Potential Melastatin family member 8), whose activation might be mediated by the neurotrophic factor artemin (ARTN) acting on its primary receptor, GFRα3. To test the hypothesis that radiation triggers release of ARTN, which results in activation of TRPM8 to cause RAP, we performed tongue-irradiation in mice that had been treated with either monoclonal anti-ARTN-neutralizing antibody or control (IgG). Lingual ARTN expression (IHC) increased after lingual irradiation, and this was mitigated by anti-ARTN treatment. Assessments of glossitis severity, body weight, and behavioral pain measures indicated that irradiation caused severe pain, which ARTN depletion failed to mitigate. However, after topical ophthalmic application of cold saline solution, tongue-irradiated anti-ARTN treated mice wiped their eyes less than their IgG-treated counterparts, and as assessed via ex vivo calcium imaging of trigeminal ganglia neurons, their afferent sensory nerves were less responsive to cold buffer. We therefore conclude that at the molecular level, ARTN depletion reduced radiation-induced cold sensitivity, but was insufficient to reduce behavioral indicators of RAP. Ongoing work in tissues from these mice is exploring whether changes in cold sensitivity correlated with TRPM8 expression, and future experiments are planned to assess: (1) whether genetic deletion of ARTN reduces RAP, and (2) if modulation of ARTN leads to upregulation of alternative TRPM8 activators. Citation Format: Faihaa A. Ahmed, Thitsana Ingkasri, Sophi Schofield, Elizabeth Wright, B. Duncan X. Lascelles, Santosh K. Mishra, Michael Nolan. The impact of artemin depletion on acute radiation-associated oral pain [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1835.