{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:58:41Z","timestamp":1791237521189,"version":"4.1.0"},"reference-count":21,"publisher":"Radiation Research Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Radiation Research"],"published-print":{"date-parts":[[2026,1,22]]},"abstract":"<jats:p>Radiation-associated pain (RAP) after head and neck cancer treatment often results in significant discomfort, yet the mechanisms underlying this pain remain poorly understood. Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) channels, known to mediate cold sensation, have been implicated in RAP. Previous studies suggested that inhibition of TRPM8 might offer a therapeutic approach for alleviating radiation-induced pain. We tested the effects of PBMC, a small molecule inhibitor of TRPM8, on radiation-induced glossitis and associated pain behaviors in C57BL\/6J mice following tongue irradiation. We evaluated the impact of phenylethyl(2-aminoethyl)(4-(benzyloxy)-3-methoxybenzyl)carbamate (PBMC) on weight loss, burrowing, grooming behavior, and nest building. Additionally, mRNA expression of TRPM8 and other relevant ion channels was assessed in the trigeminal ganglion (TG) using qRT-PCR and in situ hybridization (ISH). Irradiated mice exhibited significant glossitis, weight loss, and altered behaviors, including impaired burrowing and grooming. PBMC treatment provided no measurable protection against glossitis and only weakly mitigated weight loss and abnormal burrowing behavior. Exposure to radiation led to downregulation of TRPM8 expression in the TG, contrasting with previous findings of upregulation. Interestingly, female mice showed greater susceptibility to RAP than males, highlighting a sex-dependent response. Our findings suggest that TRPM8 inhibition with PBMC does not alleviate radiation-induced pain or glossitis in the C57BL\/6J murine model. The observed downregulation of TRPM8 expression challenges prior assumptions, and our results suggest that compensatory mechanisms or model-specific factors may contribute to the failure of PBMC to impact pain outcomes. Future studies incorporating genetic models and evaluating protein expression are necessary to better understand the role of TRPM8 in radiation-induced pain and to explore more effective therapeutic strategies.<\/jats:p>","DOI":"10.1667\/rade-25-00026.1","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T19:10:04Z","timestamp":1770837004000},"page":"234-243","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological Blockade of TRPM8 Ion Channels Fails to Reduce Behavioral and Biological Markers of Acute Oral Pain in Irradiated C57BL\/6J Mice"],"prefix":"10.1667","volume":"205","author":[{"given":"Joshua J.","family":"Wheeler","sequence":"first","affiliation":[{"name":"Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thitsana","family":"Ingkasri","sequence":"additional","affiliation":[{"name":"Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Hao","family":"Lai","sequence":"additional","affiliation":[{"name":"Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaylen","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Marcus","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophi J.","family":"Schofield","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald M.","family":"Roback","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Rex Cancer Center, Raleigh, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne M.","family":"Mowery","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. Duncan","family":"X. Lascelles","sequence":"additional","affiliation":[{"name":"Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh K.","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Nolan","sequence":"additional","affiliation":[{"name":"Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1243","reference":[{"key":"1","doi-asserted-by":"crossref","unstructured":"TY Seiwert, JK Salama, EE Vokes,  \"Nat Clin Pract Oncol.\"  4, \"The chemoradiation paradigm in head and neck cancer.\" 156 (2007)","DOI":"10.1038\/ncponc0750"},{"key":"3","doi-asserted-by":"crossref","unstructured":"A Carlotto, VL Hogsett, EM Maiorini, et al.  \"Pharmacoeconomics.\"  31, \"The economic burden of toxicities associated with cancer treatment: review of the literature and analysis of nausea and vomiting, diarrhoea, oral mucositis and fatigue.\" 753 (2013)","DOI":"10.1007\/s40273-013-0081-2"},{"key":"4","doi-asserted-by":"crossref","unstructured":"S Zenda, K Matsuura, H Tachibana, et al.  \"Radiother Oncol.\"  101, \"Multicenter phase II study of an opioid-based pain control program for head and neck cancer patients receiving chemo-radiotherapy.\" 410 (2011)","DOI":"10.1016\/j.radonc.2011.09.016"},{"key":"7","doi-asserted-by":"crossref","unstructured":"Y Lai, W B\u00e4umer, C Meneses, et al.  \"Radiat Res.\"  196, \"Irradiation of the normal murine tongue causes upregulation and activation of transient receptor potential (TRP) ion channels.\" 331 (2021)","DOI":"10.1667\/RADE-21-000103.1"},{"key":"8","doi-asserted-by":"crossref","unstructured":"Y Karashima, K Talavera, W Everaerts, et al.  \"Proc Natl Acad Sci U S A.\"  106, \"TRPA1 acts as a cold sensor in vitro and in vivo.\" 1273 (2009)","DOI":"10.1073\/pnas.0808487106"},{"key":"11","doi-asserted-by":"crossref","unstructured":"Y Qi, H Gong, Z Shen, et al.  \"Eur J Med Chem.\"  282, \"TRPM8 and TRPA1 ideal targets for treating cold-induced pain.\" 117043 (2025)","DOI":"10.1016\/j.ejmech.2024.117043"},{"key":"12","doi-asserted-by":"crossref","unstructured":"WM Knowlton, RL Daniels, R Palkar, et al.  \"PLoS One.\"  6, \"Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice.\" e25894 (2011)","DOI":"10.1371\/journal.pone.0025894"},{"key":"13","doi-asserted-by":"crossref","unstructured":"K Diao, TP Nguyen, AC Moreno, et al.  \"Head Neck.\"  43, \"Stereotactic body ablative radiotherapy for reirradiation of small volume head and neck cancers is associated with prolonged survival: Large, single-institution, modern cohort study.\" 3331 (2021)","DOI":"10.1002\/hed.26820"},{"key":"14","doi-asserted-by":"crossref","unstructured":"M Swain  and S Ghosh-Laskar  \"Oral Oncology.\"  116, \"Stereotactic body radiotherapy (SBRT) for primary non-metastatic head and neck cancer: When less is enough.\" 105265 (2021)","DOI":"10.1016\/j.oraloncology.2021.105265"},{"key":"17","unstructured":"CSM. 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