Salmon calcitonin (sCT), a hormone shown to modulate calcium in the periphery modulated free, intracellular calcium, ([Ca++]i), in mouse brain synaptosomes as measured by changes in fura-2-mediated fluorescence. A 5-min incubation of synaptosomes with sCT produced an increase in the basal levels of [Ca++]i and an increase in KCl-stimulated levels of [Ca++]i. A 5-min pretreatment of mice with intraventricularly administered sCT antagonized morphine-induced antinociception in the tail-flick test, and facilitated naloxone antagonism of morphine. Conversely, pretreatment of synaptosomes for 1 h with salmon CT produced a decrease in depolarization-stimulated levels of [Ca++]i. The sCT-induced decrease in the stimulated rise in [Ca++]i at 1 h correlated temporally to sCT-induced antinociception in vivo. The effects of sCT in the electrically stimulated guinea pig ileum bioassay appeared to correlate to sCT effects in vivo. The data indicate that calcitonin may function as a neuromodulator via modulation of Ca++ within the central nervous system.