Reactive oxygen species scavengers ameliorate mechanical allodynia in a rat model of cancer-induced bone pain

Cancer-induced bone pain (CIBP) is a frequent complication in patients suffering from bone metastases. Previous studies have demonstrated a pivotal role of reactive oxygen species (ROS) in inflammatory and neuropathic pain, and ROS scavengers exhibited potent antinociceptive effect. However, the role of spinal ROS remains unclear. In this study, we investigated the analgesic effect of two ROS scavengers in a well-established CIBP model. Our results found that intraperitoneal injection of N-tert-Butyl-alpha-phenylnitrone (PBN, 50 and 100 mg/kg) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol, 100 and 200 mg/kg) significantly suppressed the established mechanical allodynia in CIBP rats. Moreover, repeated injection of PBN and Tempol showed cumulative analgesic effect without tolerance. However, early treatment with PBN and Tempol failed to prevent the development of CIBP. Naive rats received repetitive injection of PBN and Tempol showed no significant change regarding the nociceptive responses. Finally, PBN and Tempol treatment notably suppressed the activation of spinal microglia in CIBP rats. In conclusion, ROS scavengers attenuated established CIBP by suppressing the activation of microglia in the spinal cord.