Early radiation-induced oral pain signaling responses are reduced with pentoxifylline treatment

Radiation-induced acute oral mucositis is associated with inflammation and pain. In other realms of pain research, nociceptors are known to be activated by inflammatory cytokines; for example, tumor necrosis factor alpha (TNF-alpha) can activate transient receptor potential ion channels on sensory neurons. But there is an unclear relationship between inflammatory cytokines and molecular mediators of pain in radiation-induced mucositis (RIM) and radiation-associated pain (RAP). In this prospective, analytical, experimental pilot study, a common drug (pentoxifylline [PTX]) was used with the goal of inhibiting TNF-alpha signaling in mice that underwent lingual irradiation to induce severe acute oral RIM/RAP. Body weight and glossitis scores were recorded daily. Eye wiping behaviors were assayed as a surrogate measure of oral discomfort (which is possible due to cross-sensitization of the mandibular and ophthalmic branches of the trigeminal nerve). Quantitative real-time reverse transcription polymerase chain reaction was performed on irradiated tongue tissue to measure changes in expression of TNF-alpha, its receptor, nuclear factor kappa-light-chain-enhancer of activated B cells, transient receptor potential vanilloid type 1 (TRPV1), and transient receptor potential vanilloid type 4 (TRPV4). Responsiveness of afferent sensory trigeminal neurons to TNF-alpha, a TRPV1 agonist (capsaicin), and a partial TRPV4 agonist (histamine) was measured via calcium imaging. Although PTX treatment did not reduce glossitis severity or mitigate weight loss in mice with RIM/RAP, it did inhibit the upregulation of TNF-alpha's receptor that normally accompanies RIM, and it also reduced neuronal responsiveness to each of the aforementioned chemical stimuli. These results provide provisional evidence that inhibition of TNF-alpha signaling with PTX treatment may serve as a useful tool for reducing pain in head and neck cancer patients.

Automated summary

This study investigated the impact of pentoxifylline (PTX) on radiation-induced acute oral mucositis and related pain, finding that PTX could inhibit the TNF-alpha signaling pathway and reduce neuronal responsiveness to chemical stimuli, potentially aiding in alleviating pain in head and neck cancer patients.