EVIDENCE FOR A ROLE OF BRADYKININ NEURONS IN THE CONTROL OF GONADOTROPIN-RELEASING-HORMONE SECRETION

The present study provides evidence of a novel neuronal pathway for th e control of GnRH secretion involving bradykinin neurons. Bradykinin n eurons were shown by immunohistochemistry to be densely localized in s everal regions of the brain including the cortex, hippocampus and supr aoptic nucleus, as well as two regions critical in the control of GnRH secretion, the organum vasculosum of the lamina terminalis and arcuat e nucleus. Bradykinin dose-dependently stimulated GnRH release from ma le and proestrous female rat hypothalami in vitro. Antagonist studies revealed that bradykinin effects are mediated by the bradykinin B-2 re ceptor. The effect of bradykinin on GnRH release is not mediated by th e classical major transmitter, glutamate, as glutamate antagonists had no effect on bradykinin stimulation of GnRH release. Rather, bradykin in appears to act directly on the GnRH neuron as bradykinin stimulated GnRH release directly from immortalized GnRH (GT1-7) neurons in vitro , and immunoblot studies revealed that the bradykinin B-2 receptor is present in GT1-7 neurons. The bradykinin B-2 receptor was also demonst rated in the rat hypothalamus and pituitary by immunoblotting. Bradyki nin-induced exocytosis of GnRH appears to involve activation of the PK C signaling pathway, as a PKC inhibitor blocked bradykinin-induced GnR H release. Finally, bradykinin neurons appear to be important mediator s of steroid signals in the hypothalamus to produce the LH surge, as c entral administration of a B-2 antagonist, but not a B-1 antagonist, s ignificantly attenuated the steroid-induced LH surge in the ovariectom ized female rat.