The present study was conducted to determine whether zinc ions are involved in the modulation of substance P release from cultured rat dorsal root ganglion (DRG) neurons. We show here that that lower concentrations (10(-8) - 10(-7) M) of zinc ions may evoke an extracellular Ca(2+) influx through L-, N-, and T-type voltage-dependent Ca(2+) channels, thereby increasing the substance P release from cultured DRG neurons, but higher concentrations (10(-6) - 10(-4) M) of zinc ions attenuate or even completely mask these responses. Zinc ions therefore seem to be an important modulator of substance P release from primary afferent neurons.