Inflammation is a protective response triggered by noxious or tissue-injuring stimuli characterized by increases in blood flow and vascular permeability, and by migration of leukocytes. The acute inflammatory response liberates, through positive feedback, factors that themselves can, over time, result in tissue injury. Therefore, appropriate down-regulation of the acute inflammatory response is an important physiological phenomenon that could prevent unnecessary tissue damage. Recently, the P.I.'s laboratory has described neural and endocrine mechanisms that appear to provide such an inhibitory control of inflammation. In the current granting period, it was demonstrated that there is a feedback inhibition of inflammation initiated by electrical or chemical activation of C-fiber afferents, which is exerted in the knee joint synovium to inibit inflammatory mediator (bradykinin (BK))-induced plasma extravasation (PE), and integral component of the inflammatory response. This circuit involves ascending spinal pathways, activation of the hypothalamo-pituitary-adrenal (HPA) axis and indirect action by corticosterone to elicit a transferable factor, present in synovial fluid that can inhibit inflammation in a naive recipient. It was also discovered that tonic afferent activity in the celiac branch of the subdiaphragmatic vagus, which carries afferents from the GI tract, potently suppresses the ability of nociceptor activation to inhibit inflammation. Preliminary data demonstrates that stress also leads to inhibition of inflammation. In the proposed experiments it will be determined whether nociceptor activity-induced inhibition of BK-PE can be produced by non-chemical activation of C-fibers, and by activation of C-fibers in different tissues and characteristics of stress activation of the HPA, sympathoadrenal and sympathetic neural axes induced inhibition of inflammation. Lastly, vagal modulation of the inhibition of inflammation will be further investigated to determine the visceral organ from which activity originates, the physiological stimuli required to produce the modulation and the role of descending antinociceptive controls and spinal opioidergic and catecholaminergic mechanisms in mediating the effect. The proposed studies will elucidate mechanisms in neural and endocrine circuits controlling inflammation and provide details of the interaction of central pathways involved in nociception, stress, HPA axis activity and processing of vagal afferent input. These studies have relevance to the understanding and eventual control of chronic inflammation in humans.