Cannabinoids have been reported to have analgesic properties in animals of acute nociception or of inflammatory and neuropathic pain models, but the mechanisms by which they exert such alleviative effects are not yet fully understood. We investigated whether the CB₁-cannabinoid-receptor agonist HU210 modulates the capsaicin-induced ⁴⁵Ca²⁺ influx and substance P like-immunoreactivity (SPLI) release in cultured rat dorsal root ganglion (DRG) cells. HU210 attenuated the capsaicin-induced ⁴⁵Ca²⁺ influx and this effect was reversed by the CB₁ antagonist AM251. Treatment of DRG cells with 100 nM bradykinin for 3 h potentiated capsaicin-induced SPLI release accompanied with the induction of cyclooxygenase-2 mRNA expression. The potentiation of SPLI release by bradykinin was reversed by HU210 or the protein kinase A (PKA) inhibitor H-89. HU210 also reduced forskolin-induced cyclic AMP production and forskolin-induced potentiation of SPLI release. These results suggest that CB₁ could inhibit either the capsaicin-induced Ca²⁺ influx or the potentiation of capsaicin-induced SPLI release by a long-term treatment with bradykinin through involvement of a cyclic-AMP-dependent PKA pathway. In conclusion, CB₁-receptor stimulation modulates the activities of transient receptor potential vanilloid receptor 1 in cultured rat DRG cells.