The study identifies N-arachidonoyl-dopamine (NADA) as an endogenous "capsaicin-like" substance in mammalian nervous tissues. NADA is found in high concentrations in the striatum, hippocampus, and cerebellum, and its biosynthesis involves the condensation of dopamine with arachidonic acid or tyrosine. NADA activates both human and rat vanilloid receptor 1 (VR1) with potency and efficacy similar to capsaicin, and it induces thermal hyperalgesia and enhances neuropeptide release from dorsal root ganglion (DRG) neurons. NADA also potently activates native VR1 in DRG neurons and hippocampal paired-pulse depression, suggesting a role in sensory processing and hippocampal plasticity. The discovery of NADA provides insights into the physiological functions of VR1 in the central nervous system.The study identifies N-arachidonoyl-dopamine (NADA) as an endogenous "capsaicin-like" substance in mammalian nervous tissues. NADA is found in high concentrations in the striatum, hippocampus, and cerebellum, and its biosynthesis involves the condensation of dopamine with arachidonic acid or tyrosine. NADA activates both human and rat vanilloid receptor 1 (VR1) with potency and efficacy similar to capsaicin, and it induces thermal hyperalgesia and enhances neuropeptide release from dorsal root ganglion (DRG) neurons. NADA also potently activates native VR1 in DRG neurons and hippocampal paired-pulse depression, suggesting a role in sensory processing and hippocampal plasticity. The discovery of NADA provides insights into the physiological functions of VR1 in the central nervous system.