We describe that an ongoing inflammatory response at one site (produced by complete Freund's adjuvant injection in the hindpaw) produces a negative feedback inhibition on plasma extravasation, produced by perfusion of the inflammatory mediator, bradykinin (160 nM), at a second site (the knee joint). This negative feedback process is abolished in rats that have been neonatally treated with capsaicin to deplete most of their unmyelinated primary afferent fibers, which suggests that this negative feedback process is mediated by activation of primary afferent fibers. Electrical stimulation of the hindpaw at intensities that excite C-fibers also inhibited bradykinin-induced plasma extravasation. Stimulation at intensities that only excite A- fibers had no effect on bradykinin-induced plasma extravasation. Platelet activating factor-induced plasma extravasation, which is not dependent on the innervation of the joint, was not inhibited by stimulation of C-fibers from the hindpaw. Acute surgical interruption of the lumbar sympathetic outflow to the hind limb (the paravertebral ganglia between L2 and L4) did not attenuate the depression of bradykinin-induced plasma extravasation produced by C-fiber stimulation. This indicates that the depression is not mediated by activity in the sympathetic outflow. Transection of the spinal cord, hypophysectomy, inhibition of corticosterone synthesis, and adrenalectomy (but not adrenal medullectomy) all prevented the inhibition of BK-induced plasma extravasation by electrical simulation, indicating that the negative feedback inhibition on plasma extravasation is dependent on an intact neuraxis and an intact hypothalamic-pituitary-adrenocortical axis. In summary, our data demonstrate a negative feedback inhibition of an inflammatory process, which is elicited by stimulation of C-fiber afferents.