Cannabinoid receptors are absent in insects

The endocannabinoid system exerts an important neuromodulatory role in mammals. Knockout mice lacking cannabinoid (CB) receptors exhibit significant morbidity. The endocannabinoid system also appears to be phylogenetically ancient–it occurs in mammals, birds, amphibians, fish, sea urchins, leeches, mussels, and even the most primitive animal with a nerve network, the Hydra. The presence of CB receptors, however, has not been examined in terrestrial invertebrates (or any member of the Ecdysozoa). Surprisingly, we found no specific binding of the synthetic CB ligands [(3)H]CP55,940 and [(3)H]SR141716A in a panel of insects: Apis mellifera, Drosophila melanogaster, Gerris marginatus, Spodoptera frugiperda, and Zophobas atratus. A lack of functional CB receptors was confirmed by the inability of tetrahydrocannabinol (THC) and HU210 to activate G-proteins in insect tissues, utilizing a guanosine-5′-O-(3-[(35)]thio)-triphosphate (GTP gamma S) assay. No orthologs of human CB receptors were located in the Drosophila genome, nor did we find orthologs of fatty acid amide hydrolase. This loss of CB receptors appears to be unique in the field of comparative neurobiology. No other known mammalian neuroreceptor is understood to be missing in insects. We hypothesized that CB receptors were lost in insects because of a dearth of ligands; endogenous CB ligands are metabolites of arachidonic acid, and insects produce little or no arachidonic acid or endocannabinoid ligands, such as anandamide.