Aprepitant mitigates paclitaxel-induced neuropathic pain in rats via suppressing inflammatory pathways in dorsal root ganglia.

Abstract

Neuropathic pain is the crucial dose-limiting side effect of paclitaxel in chemotherapy patients that negatively impacts the quality of life and survival. Currently, no effective treatment option is available. Aprepitant, a well-established chemotherapy antiemetic performing neurokinin-1 receptor antagonism, shows analgesic effects in some pain models. We studied aprepitant analgesic effects on the paclitaxel-induced neuropathic pain model in rats besides inflammatory markers assessment. Rats intraperitoneally received paclitaxel, reaching the cumulative paclitaxel dose of 8 mg/kg. Aprepitant was orally administered every alternate day between days 2 and 14, with a prescribed dosage of 10 or 20 mg/kg. The evaluation of mechanical allodynia and cold hyperalgesia involved the measurement of paw withdrawal threshold and acetone test score on days 0, 7, and 14. On day 14, paw licking latency was measured using a hot plate test before scarification and tissue collection for interleukin 1β, tumor necrosis factor α, and nuclear factor kappa B (NF-kB) evaluation. Paclitaxel induced neuropathy as indicated by a lowered hind paw withdrawal threshold in the Von Frey test, a higher score in the acetone test, and shortened hot plate latency. Aprepitant effectively alleviated cold and thermal hyperalgesia as well as mechanical allodynia. Moreover, aprepitant administration significantly reversed paclitaxel-mediated elevation of proinflammatory cytokines levels in dorsal root ganglia. In addition, aprepitant application suppressed the protein expression of NF-kB in the dorsal root ganglia of paclitaxel-treated rats, as revealed by western blot analysis. Aprepitant treatment ameliorates neuropathy induced by paclitaxel, which is associated with decreasing proinflammatory cytokines and NF-kB expression.