1. Effects of cannabinoid agonists on the serotonin (5-HT)3 receptor-mediated current were investigated in rat nodose ganglion neurons. Anandamide, Win 55212-2, and CP55940 inhibited the 5-HT-induced current in a concentration dependent manner. IC50 values were 190, 310, and 94 nM for anandamide, Win 55212-2, and CP55940, respectively, and 1.6 microM for the nonpsychoactive enantiomer CP56667. This inhibition was slowly developing, noncompetitive, not dependent on membrane potential, and not affected by adenosine 3',5'-cyclic monophosphate (cAMP) analogues, guanosine-5'-O-(2-thiodiphosphate) (GDP-beta-S), and opioid receptor antagonist naltrexone. These data suggest that 5-HT3 receptor ion-channel is a site acted upon by cannabinoid agonists in the nervous system, and the action of cannabinoid agonists on 5-HT3 receptors may be a possible mechanism for some of the behavioral effects of cannabinoids, such as antiemesis and analgesia.