Our laboratory has published a new study in Scientific Reports revealing how the endocannabinoid precursor 20:4-NAPE influences pain signaling at the level of sensory neurons. Pain perception is largely determined by the excitability of dorsal root ganglion (DRG) neurons, which transmit signals from the periphery to the spinal cord. The compound 20:4-NAPE, a natural precursor of anandamide, can be converted by the enzyme NAPE-PLD into active endocannabinoids, which then act on cannabinoid (CB1) and vanilloid (TRPV1) receptors.
In our experiments, we showed that the effects of 20:4-NAPE depend strongly on its concentration. At lower doses, 20:4-NAPE reduced neuronal excitability and produced analgesic effects in animal models, suggesting a protective role against pain. In contrast, higher concentrations increased excitability and even triggered mechanical allodynia, a heightened sensitivity to normally non-painful stimuli. Importantly, both the inhibitory and excitatory effects were prevented by blocking NAPE-PLD, demonstrating that the observed outcomes are mediated through endogenous production of anandamide and its interaction with CB1 and TRPV1 receptors.
These findings highlight the dual role of 20:4-NAPE in pain modulation: it can either dampen or enhance pain sensitivity, depending on dosage. This complexity underscores why previous drug trials targeting the endocannabinoid system have often failed, but it also opens new opportunities. By carefully controlling 20:4-NAPE pathways, it may be possible to design more precise analgesic therapies that avoid unwanted side effects.
Our study therefore advances the understanding of endocannabinoid biology and points to 20:4-NAPE as a promising therapeutic target for the development of next-generation pain treatments.
Bhattacharyya; Anirban – Vasconcelos; Daniel – Špicarová; Diana – Paleček; Jiří 20:4-NAPE induced changes of mechanical sensitivity and DRG neurons excitability are concentration dependent and mediated via NAPE-PLD. Scientific Reports. 2025; 15(1); 14131.
