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This study investigated the modulatory effect of synthetic cannbinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-Hr3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique.The results showed that:(!) The majority of examined neurons (78.70％) were sensitive to 5-HT (3-300 μmol/L).5-HT induced inward currents in a concentrationdependent manner and the currents were blocked by ICS 205-930 (1 μmol/L),a selective antagonist of the 5-HT3 receptor; (2) Pre-application of WIN55,212-2 (0.01-1 μmol/L) significantly inhibited I5-HT3 reversibly in concentration-dependent and voltage-independent manners.The concentration-response curve of 5-HT3 receptor was shifted downward by WIN55,212-2 without any change of the threshold value.The EC50values of two curves were very close (17.5±4.5) μmol/L vs.(15.2±4.5) μmol/L and WIN55,212-2 decreased the maximal amplitude of I5-HI3 by (48.65±4.15)％; (3) Neither AM281,a selective CBI receptor antagonist,nor AM630,a selective CB2 receptor antagonist reversed the inhibition of I5-HT3by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application,inhibitory effect was gradually increased and the maximal inhibition took place at 90 s,and the inhibition remained at the same level after 90 s.We are led to concluded thatWIN55,212-2 inhibited I5-Hr3 significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I5-HT3 by WIN55,212-2.Moreover,WIN55,212-2 is not an open channel blocker (OCB) of 5-HT3 receptor.WIN55,212-2 significantly inhibited 5-HT-activated currents in a non-competitive manner.The inhibition of I5-HT3 by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212-2,but the mechanism by which WIN55,212-2 inhibits I5-HT3 warrants further investigation.