Activation of cannabinoid receptor type 1 on presynaptic neurons is postulated to suppress neu-rotransmission by decreasing Ca2+influx through high voltage-gated Ca2+channels. However, recent studies suggest that cannabinoids which activate cannabinoid receptor type 1 can increase neurotransmitter release by enhancing Ca2+influx in vitro. The aim of the present study was to investigate the modulation of intracellular Ca2+concentration by the cannabinoid receptor type 1 agonist anandamide, and its underlying mechanisms. Using whole cell voltage-clamp and calcium imaging in cultured trigeminal ganglion neurons, we found that anandamide directly caused Ca2+inlfux in a dose-dependent manner, which then triggered an increase of intracellular Ca2+concentration. The cyclic adenosine and guanosine monophosphate-dependent protein kinase systems, but not the protein kinase C system, were involved in the increased intracellular Ca2+concentration by anandamide. This result showed that anandamide increased intracellu-lar Ca2+concentration and inhibited high voltage-gated Ca2+channels through different signal transduction pathways.