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Background and purpose: N-arachidonoyl 5-HT (NA-5HT) has anti-nociceptive effects reported to be mediated by inhibitory actions at the transient receptor potential vanilloid receptor 1 (TRPV1) and fatty acid amide hydrolase (FAAH). Anandamide and N-arachidonoyl dopamine (NA-DA), endocannabinoids that activate TRPV1 or are metabolized by FAAH, also inhibit T-type calcium channels (I Ca). T-type ICa are expressed by many excitable cells, including neurons involved in pain detection and processing. We sought to determine whether NA-5HT also modulates T-type ICa. Experimental approach: Human recombinant T-type ICa (CaV3 channels) expressed in HEK 293 cells were examined using standard whole-cell voltage-clamp electrophysiology techniques. Key results: NA-5HT completely inhibited Ca V3 channels with a rank order of potency (pEC50) of CaV3.1 (7.4) > CaV3.3 (6.8) ¥ CaV3.2 (6.6). The effects of NA-5HT were voltage-dependent, and it produced significant hyperpolarizing shifts in CaV3 steady-state inactivation relationships. NA-5HT selectively affected CaV3.3 channel kinetics. Conclusions and implications: NA-5HT increases the steady-state inactivation of CaV3 channels, reducing the number of channels available to open during depolarization. These effects occur at NA-5HT concentrations at or below those at which NA-5HT affects TRPV1 receptors and FAAH. NA-5HT is one of the most potent inhibitors of T-type ICa described to date, and it is likely to exert some of its biological effects, including anti-nociception, via inhibition of these channels.