The effect of ICS 205-930 (ICS), a specific 5-HT3 antagonist, was studied on carrageenan (CAR)-induced rat paw inflammation to assess the involvement of endogenous released serotonin (5-HT) in the observed hyperalgesia. Studies were performed using a behavioural test, measuring the threshold stimulus necessary to elicit vocalization by gradually increasing pressure applied to the paw. When administered (s.c., in the CAR-injected paw) either 20 min before, simultaneously or 20 min after CAR, ICS (10(-11) mol/kg, i.e., 3.2 ng/kg) completely prevented the hyperalgesia in both the injected and non-injected hind paws. This effect was prolonged for 90 min, equivalent to the effect on CAR on 5-HT release. Moreover, ICS increased the vocalization threshold over the pre-drug values in normal and CAR-treated rats when injected both 20 min before and simultaneously with the polysaccharide. On the contrary, it did not reduce the hyperalgesia, when injected 2 h after CAR. ICS had no effect at any time of administration on paw oedema. These results suggest that the early inflammatory sensitization of peripheral nociceptors is mainly dependent on the release of serotonin and that the hyperalgesic effect of the monoamine involves 5-HT3(M) receptors which do not seem to be involved in the early development of oedema.