Vagal afferent nerve fibres are involved in the transmission to the central nervous system of information relating to food intake and immune reactions. Leptin is involved in the control of food intake and has specific receptors in afferent vagal neurones. To investigate the role of these receptors, we studied the effects of leptin on single vagal afferent activities from intestinal mechanoreceptors in anaesthetized cats. The activity of 35 intestinal vagal mechanoreceptors was recorded by means of glass microelectrodes implanted in the nodose ganglion. Leptin (10 μg), administered into the artery irrigating the upper part of the intestine, induced activation in 17 units (P < 0.001), inhibition in 8 units (P < 0.05), and had no effect on 10 units. The excitatory effects of leptin were blocked by the endogenous interleukine-1β receptor antagonist, (Il-1ra, 250 μg, i.a.). Cholecystokinin (CCK, 10 μg, i.a.) induced an activatory response only in the two types of units which were responsive to leptin alone. When leptin was administered after CCK, its excitatory effects were enhanced and its inhibitory effects were blocked, whereas it had no effect on the units which were not affected by leptin alone. The interactions between leptin and CCK are specific ones, since other substances (phenylbiguanide, a serotoninergic agonist; substance P) known to activate the mechanoreceptors did not modify the effects of leptin. These results indicate that leptin appears to play a role in the control of immune responses and food intake via intestinal vagal afferent nerve fibres and that there is a functional link between leptin and Il-1β.