We have investigated the effect of capsaicin on Ca 2+ release from the intracellular calcium stores. Intracellular calcium concentration ([Ca 2+ ] i ) was measured in rat dorsal root ganglion (DRG) neurons using microfluorimetry with fura-2 indicator. Brief application of capsaicin (1 μM) elevated [Ca 2+ ] i in Ca 2+ -free solution. Capsaicin-induced [Ca 2+ ] i transient in Ca 2+ -free solution was evoked in a dose-dependent manner. Resiniferatoxin, an analogue of capsaicin, also raised [Ca 2+ ] i in Ca 2+ -free solution. Capsazepine, an antagonist of capsaicin receptor, completely blocked the capsaicin-induced [Ca 2+ ] i transient. Caffeine completely abolished capsaicin-induced [Ca 2+ ] i transient. Dantrolene sodium and ruthenium red, antagonists of the ryanodine receptor, blocked the effect of capsaicin on [Ca 2+ ] i . However, capsaicin-induced [Ca 2+ ] i transient was not affected by 2-APB, a membrane-permeable IP 3 receptor antagonist. Furthermore, depletion of IP 3 -sensitive Ca 2+ stores by bradykinin and phospholipase C inhibitors, neomycin, and U-73122, did not block capsaicin-induced [Ca 2+ ] i transient. In conclusion, capsaicin increases [Ca 2+ ] i through Ca 2+ release from ryanodine-sensitive Ca 2+ stores, but not from IP 3 -sensitive Ca 2+ stores in addition to Ca 2+ entry through capsaicin-activated nonselective cation channel in rat DRG neurons.