Noxious stimuli inhibit inflammation by activating neuroendocrine stress axes, an effect that is potently attenuated by ongoing activity in subdiaphragmatic vagal afferents. Because this vagal afferent activity is carried in the cliac and cliac accessory branches of the subdiaphragmatic vagus, we tested the hypothesis that the activity arises from vagal afferents that innervate a proximal segment of the gastrointestinal tract. Surgical removal of the duodenum, but not the stomach, produces a marked (six orders of magnitude) leftward shift in the dose-response curve for intra-plantar capsaicin-induced inhibition of synovial plasma extravasation induced by the potent inflammatory mediator bradykinin, in the knee joint; this is similar in magnitude to the inhibition produced by subdiaphragmatic or by cliac plus cliac accessory branch vagotomy (J. Physiol. 498:473-481, 1997). Fasting, to unload mechanically sensitive polymodal afferents in the proximal gastrointestinal tract produces a similar leftward shift in the dose- response curve for the inhibitory effect of capsaicin, an effect that is reversed by balloon distension in the duodenum in fasted rats, whilst balloon distension post- vagotomy had no effect. These results suggest that activation of mechanically sensitive vagal afferents in the duodenum contributes vagal afferent activity that modulates neuroendocrine control of the inflammatory response.