Involvement of the NO/cyclic GMP pathway in bradykinin-evoked pain from veins in humans

Cyclic GMP is probably a second messenger in vascular nociceptors that are excited by nitric oxide (NO), because NO is known to activate the guanylate cyclase. If so, inhibition of this enzyme should render nociceptors insensitive to algesics that act via NO. To test this hypothesis, the effect of the specific guanylate cyclase inhibitor methylene blue was studied on bradykinin-evoked, i.e. NO-mediated pain and, for control, on mechanically-evoked pain, which is probably not mediated by NO. In eight subjects, pain was evoked from isolated hand vein segments by either injection of bradykinin (1 x 10(-6) M) or noxious balloon distention. Pretreatment of the vein segments with methylene blue inhibited bradykinin-evoked pain in a concentration-dependent manner and abolished pain at a concentration of 1 x 10(-3) M. Methylene blue had no effect on mechanically evoked pain. Tachyphylaxis to intravenously applied bradykinin was not observed. These results are consistent with the hypothesis that cyclic GMP plays a role in the transduction of NO-mediated noxious stimuli in vascular nociceptors in humans.