Pentoxifylline Ameliorates Mechanical Hyperalgesia in a Rat Model of ChemotherapyInduced Neuropathic Pain

Abstract

Background: Chemotherapy-induced neuropathic pain is difficult to treat. Pentoxifylline inhibits the production of inflammatory cytokines including tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Objective: The aims of our study were to investigate the analgesic and preventive effects of pentoxifylline on paclitaxel-induced neuropathic pain in rats and to identify its mechanisms of action. Study Design: Controlled animal study. Methods: Neuropathic pain was induced with intraperitoneally injected paclitaxel on 4 alternate days in male Sprague-Dawley rats. Pentoxifylline was administered systemically as a single injection and a continuous infusion before or after the injection of paclitaxel. The mechanical threshold for allodynia was measured by using von Frey filaments. Protein levels and localization of inflammatory cytokines were performed by using Western blotting and immunohistochemistry, respectively. Results: After the rats developed neuropathic pain behavior, a single intraperitoneal injection and continuous infusion of pentoxifylline ameliorated paclitaxel-induced mechanical allodynia. In addition, systemic infusion of pentoxifylline in the early phase of the development of pain behavior delayed the onset of paclitaxel-induced pain behavior. Paclitaxel increased the levels of the catalytic subunit α of protein kinase A, phosphorylated nuclear factor κB, TNF-α, and IL-1β in the lumbar dorsal root ganglia. Pentoxifylline decreased the paclitaxel-induced TNF-α and IL1β levels. In addition, IL-1β was expressed in neurons and satellite cells in the lumbar dorsal root ganglia after paclitaxel. Limitations: Although this study was performed in the animal model by well-designed manner, clinical study will be needed to confirm the analgesic effect of pentoxifylline. Conclusion: Pentoxifylline alleviated chemotherapy-induced neuropathic pain in rats by reducing the levels of inflammatory cytokines in dorsal root ganglia and may be effective chemotherapyinduced neuropathic pain in patients. Key words: Chemotherapy, chronic pain, inflammatory cytokines, neuropathic pain, paclitaxel, pain behavior, pain treatment, pentoxifylline, phosphodiesterase inhibitor