Involvement of Protease-Activated Receptor 2 in Nociceptive Behavior in a Rat Model of Bone Cancer

Treatment for bone cancer pain remains a clinical challenge due to a poor understanding of the underlying mechanisms. Protease-activated receptor 2 (PAR2), a receptor for inflammatory proteases, has been implicated in nociceptive signaling under both normal and pathologic pain states. However, little is known of the role of PAR2 in cancer-induced bone pain. Here we investigated the potential role of PAR2 in a rat model of bone cancer pain. The model of bone cancer pain was induced by inoculating Walker 256 into the tibia bone cavity of rats and verified by X-ray imaging, pathology, and behavior assessments. The rats with bone cancer exhibited marked mechanical allodynia, thermal hyperalgesia, and signs of spontaneous nocifensive behavior. Subcutaneous administration of the PAR2 antagonist FSLLRY-NH2 almost completely abolished mechanical allodynia and thermal hyperalgesia but had no effects on spontaneous pain behavior in the rats with bone cancer. Immunohistochemical study revealed that the expression of PAR2 was significantly increased in large- and medium-sized dorsal root ganglia (DRG) neurons but not in small-sized neurons after Walker 256 inoculation. These results suggest that the increased expression of PAR2 in the DRG may contribute to the development of mechanical allodynia and thermal hyperalgesia associated with bone cancer rats. PAR2 might become a novel target for the treatment of pain in patients with bone cancer.