Sensitization of vanilloid receptor 1 induced by bradykinin via the activation of second messenger signaling cascades in rat primary afferent neurons

Abstract

Vanilloid receptor 1 was recently reported to play an important role in hyperalgesia, but the mechanisms by which this receptor is activated by endogenous inflammatory mediators, such as bradykinin and nerve growth factor, are not yet fully understood. Here, we investigated whether bradykinin, which is a pain-producing inflammatory mediator, sensitizes vanilloid receptor 1 by inducing the activation of cyclooxygenases, phospholipase C and phospholipase A2 in rat dorsal root ganglion cells. We demonstrated this using 45Ca2+ uptake and inositol phosphates accumulation assays, bradykinin activates phospholipase C and cyclooxygenase-1 through the bradykinin B2 receptor. The bradykinin B2 receptor then sensitizes vanilloid receptor 1 activity by facilitating non-selective Ca2+ channel activity, increasing the intracellular Ca2+ concentration from the extracellular pool. These methods would be useful for screening new drugs for activity at vanilloid receptor 1. These data suggest that endogenous substances produced by several enzymes may be capable of producing a synergistic response involving the vanilloid receptor 1.