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

Abstract

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‐α) 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‐α 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‐α, 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‐α, 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‐α’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‐α signaling with PTX treatment may serve as a useful tool for reducing pain in head and neck cancer patients.

Radioprotective countermeasures for radiation injury (Review)

“…PTX can also decrease the risk of radiation-induced oral mucositis after oral administration. In an experimental pilot study, PTX suppressed TNF receptor upregulation and neuronal responsiveness in patients with RTOM ( 55 ). Similarly, radiotherapy combined with PTX and vitamin E reduced the incidence of severe oral mucositis and dysphagia after adjusting for age ( 56 ).…”

Brief research report: Repurposing pentoxifylline to treat intense acute swimming–Induced delayed-onset muscle soreness in mice: Targeting peripheral and spinal cord nociceptive mechanisms

“…Ptx has been marketed for other purposes such as leprosy ( Legendre et al, 2012 ). Ptx has been tested in several preclinical rodent models of neuropathic pain, such as chemotherapy, chronic constriction injury, and spinal nerve transection ( Liu et al, 2007 ; Mika et al, 2007 ; Kim et al, 2016 ); inflammatory pain ( Vale et al, 2004 ); radiation-induced pain ( Price et al, 2021 ); and bone fracture–induced complex regional pain syndrome ( Wei et al, 2009 ). Ptx has also shown positive effects in the treatment of human lumbar disc herniation–induced radicular pain ( Tarabay et al, 2022 ).…”

PTX Treatment of Colon Cancer: Mode of Action Based on Tumor Marker and Cytokine Kinetics

“…It has been reported that the combination of PTX and vitamin E (7) reduces the severity of radiation-induced oral mucositis and dysphagia in head and neck cancer patients (8,9). In addition, it has been suggested that PTX reduces chemotherapy-induced stomatitis and osteonecrosis, through inflammatory cytokine reduction (8)(9)(10)(11)(12).…”