The role of tight junctions in modulating responses from chorda tympani (taste) and lingual (general sensory) nerves are clarified in regard to their responses to salts. Chorda tympani (CT) responses elicited by organic sodium salts require greater Na+ concentrations to elicit the same magnitude of response as NaCl. These data can be understood in terms of the organic anions (compared with Cl-) producing larger liquid-junction potentials across tight junctions between taste cells which, in turn, reduces Na+ influx into taste cells via amiloride-inhibitable channels. The anion contribution to the CT response to different Na+ salts can be eliminated (or enhanced) by voltage clamping the tongue with negative (with respect to the serosal solution) potentials. Whole nerve recordings from the lingual branch of the trigeminal nerve elicited by NaCl (and other salts) were reversibly inhibited by the tight junction blocker, LaCl3. These data suggest that small hydrophilic molecules elicit responses from trigeminal fibers by diffusing across tight junctions between epithelial cells and altering the composition of the extracellular space.