NEGATIVE FEEDBACK NEUROENDOCRINE CONTROL OF THE INFLAMMATORY RESPONSEIN RATS

We describe that an ongoing inflammatory response at one site (produce d by complete Freund's adjuvant injection in the hindpaw) produces a n egative feedback inhibition on plasma extravasation, produced by perfu sion of the inflammatory mediator, bradykinin (160 nM), at a second si te (the knee joint). This negative feedback process is abolished in ra ts 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 afferen t fibers. Electrical stimulation of the hindpaw at intensities that ex cite 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-in duced plasma extravasation, which is not dependent on the innervation of the joint, was not inhibited by stimulation of C-fibers from the hi ndpaw. Acute surgical interruption of the lumbar sympathetic outflow t o the hind limb (the paravertebral ganglia between L(2) and L(4)) did not attenuate the depression of bradykinin-induced plasma extravasatio n 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 synthes is, and adrenalectomy (but not adrenal medullectomy) all prevented the inhibition of BK-induced plasma extravasation by electrical simulatio n, indicating that the negative feedback inhibition on plasma extravas ation is dependent on an intact neuraxis and an intact hypothalamic-pi tuitary-adrenocortical axis. In summary, our data demonstrate a negati ve feedback inhibition of an inflammatory process, which is elicited b y stimulation of C-fiber afferents. It is mediated by ascending pathwa ys in the spinal cord, and probably the hypothalamic-pituitary-adrenoc ortical axis.