Involvement of TRPV1 in bone cancer pain : development of novel strategies for treating cancer pain

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1.Interaction of ET-1 with TRPV1The previous study showed that an ETA antagonist decreased bone cancer pain, but its mechanisms have been unclear. However, the mechanisms of the nociceptive action of ET-1 have not been fully elucidated. In this study, we examined the functional interaction of ET-1 with TRPV1 using patch clamp and behavioral analyses. In voltage-clamp experiments, the responses of TRPV1 to capsaicin, heat and proton were sensitized in the presence of ET-1 in a PKC-dependent manner. Western blot analysis revealed that ET-1 evoked phosphorylation of TRPV1 in HEK293 cells expressing TRPV1 and ETA. ET-1-induced potentiation of responses to capsaicin was also observed in DRG neurons. In behavioral analyses, ET-1-induced thermal hyperalgesia was abolished in mice lacking TRPV1. These findings indicate that TRPV1 is an important molecule that is involved in ET-1-induced hyperalgesia.2.Bone cancer increases transient receptor potential vanilloid subfamily 1 expression within di … More stinct subpopulations of dorsal root ganglion neuronsWe evaluated the analgesic effects of pharmacological blockade of TRPV1 using the potent TRPV1 antagonist 5-iodoresiniferatoxin (I-RTX) and examined whether bone cancer can change TRPV1 expression and distribution in the primary sensory neurons in a mouse model of bone cancer pain. The bone cancer-related pain behaviors were significantly reduced by intraperitoneal administration of I-RTX, compared to vehicle. Western blot and RT-PCR analyses revealed that TRPV1 level was significantly increased in DRGs ipsilateral to sarcoma implantation. Immunohistochemical analysis showed that implantation of osteosarcoma induced not only an increase in the percentage of TRPV1-positive neurons among DRG neurons but also an overall shift in the d stribution of area of profiles to the right. Colocalization study showed that the percentages of colocalization of TRPV1 with NF200 and CGRP but not IB4 among DRG neurons in mice with oseteosarcoma implantation were increased compared to those in sham mice. In conclusion, TRPV1 activation plays a critical role in the generation of bone cancer pain, and bone cancer increases TRPV1 expression within distinct subpopulation of DRG neurons.These findings may lead to novel strategies for the treatment of bone cancer pain. Less