The endocannabinoid system in mammals plays a role in many physiological functions and is an important emerging therapeutic target. Cannabinoid receptors have been identified in many different species, including some invertebrates, but they have not been detected in C. elegans. We have now identified components of an endocannabinoid system in C. elegans and find that it interacts with the insulin signaling pathway to modify dauer formation. In a chemical screen for suppressors of dauer formation we identified a synthetic antagonist of the mammalian cannabinoid receptor as a potent suppressor of the Daf-c phenotype of
daf-2(
e1368). The activity of this compound, and other synthetic cannabinoids, prompted us to take a biochemical approach to defining a worm endocannabinoid system, with a focus on identifying endogenous cannabinoid ligands (endocannabinoids). Analysis of worm lipid extracts by gas chromatography-mass spectrometry (GC-MS) identified a number of fatty acid ethanolamides that are structurally similar to mammalian endocannabinoid ligands. We find that endocannabinoid levels are reduced in
daf-2(
e1368) mutants under dauer inducing conditions and that endocannabinoid treatment is sufficient to promote reproductive growth in these animals, similar to the effects of synthetic cannabinoids. We also find that levels of endocannabinoids are elevated following treatment with a chemical inhibitor of fatty acid amide hydrolase (FAAH), an enzyme involved in endocannabinoid degradation and inactivation, and that RNAi of the putative worm FAAH gene has a similar effect. Overexpression of this putative C. elegans FAAH gene in wild type animals results in a profound developmental delay, further supporting a role for endocannabinoids in reproductive growth. Finally,
daf-2 mutants carrying extra copies of this FAAH gene under heterologous transcriptional control are defective in dauer exit, suggesting a role for endocannabinoids in dauer recovery. In summary these data suggest that endocannabinoids function in C. elegans to promote reproductive growth either under normal conditions or following recovery from dauer arrest. The lack of obvious cannabinoid receptors in the worm suggest the existence of a novel C. elegans receptor, whose identity may shed light on the novel receptors predicted to exist in mammals. Finally the identification of an endocannabinoid system in nematodes now brings the strengths of C. elegans as a major model system to the study of endocannabinoid physiology.