Fatty Acid Pathways Regulate Thermal Nociception in Caenorhabditis elegans

Chronic pain remains a major unmet medical challenge, and lipid signaling pathways have emerged as key modulators of nociception. Using Caenorhabditis elegans as a genetically tractable model, we investigated how fatty acid composition influences thermal avoidance behavior. Mutant strains lacking functional desaturase enzymes (elo-1, fat-1, fat-2, fat-3, fat-4, fat-6/fat-7), and consequently depleted in polyunsaturated fatty acids (PUFAs) such as arachidonic acid, displayed significantly reduced sensitivity to noxious heat compared to wild-type animals. These findings indicate that intact PUFA biosynthesis is essential for normal thermal nociception in C. elegans. Given that arachidonic acid is a precursor of endocannabinoids (AEA and 2-AG) known to modulate TRPV1-dependent pain signaling, our results suggest that a conserved lipid-based mechanism regulates heat avoidance in nematodes. This study establishes a functional link between fatty acid metabolism and nociceptive behavior, providing a powerful platform to explore metabolic modulation of pain pathways.