The regulatory role of nitric oxide in capsaicin-induced 45Ca2+ accumulation in dorsal root ganglion neuronal cultures was investigated. Capsaicin-activated calcium entry was subject to complicated tuning by NO-releasing agents sodium nitroprusside, spermine/NO complex and NO synthase inhibitor NG-nitro-L-arginine methyl ester in concentration and stimulation protocol-dependent manner. In contrast, these agents failed to change depolarization-induced calcium influx. In experiments using dithiothreitol and 5,5-dithio-bis-2-nitrobenzoic acid this modulation was independent of the oxidizing action of NO. It is suggested that NO exerts a novel feedback modulatory effects on capsaicin-induced calcium entry into rat DRG neurons.