Mechanisms of cancer pain at the level of the peripheral nerve system

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Background: Increasing evidence indicates that endothelin-1 (ET-1) has a role for peripheral nociceptive signaling in animals and humans. However, the mechanisms of the nociceptive effects of ET-1 have not been fully understood. The current study investigated the effects of ET-1 on the response of cultured adult mice dorsal root ganglion (DRG) neurons to capsaicin using intracellular calcium measurement and histochemical analyses.Methods: DRG were harvested from adult male C57B6N mice and were cultured. With a digital image analysis system, we detected the [Ca^<2+>]_i image of cultured DRG cells after loading with fura-2 AM. In addition, co-localization of protein kinase C (PKCL) with transient receptor potential Vi (TRPV1) and the translocation of PKCD were investigated using immunohistochemical methods.ResultsET-1 (10 nM) enhanced an increase in [Ca^<2+>]_i by capsaicin (10 nM) from 87.6 +- 11.6 nM to 414.8 +- 62.3 nM. The inhibition of endothelin A receptor significantly suppressed the enhancing effect of ET-1. In addition, a nonselective PKC inhibitor significantly suppressed the enhancing effect of ET-1. A myristoyl-tagged membrane-permeant-PKCD V1.2 inhibitory peptide also significantly suppressed the enhancing effect of ET-1. In the immunocytochemical study, PKCD immunoreactivity was found in most of TRPV1-positive neurons. After ET -1 application, PKCD immunoreactivity was observed to be translocated from the cytosol to the cell membrane in TRPV1-positive neurons,ConclusionOur results indicate that ET-1 enhances the response of DRG neurons to capsaicin in a PKC dependent manner. Our findings may lead to a new strategy to treat pain associated with ET-1.