The Endocannabinoid System (ECS) is a complex cell-signaling network that regulates biological balance, or homeostasis, across many animal species. This system is composed of endogenous lipid-based signaling molecules, the enzymes that synthesize and degrade them, and two primary protein receptors. The two canonical receptors, Cannabinoid Receptor Type 1 (CB1) and Cannabinoid Receptor Type 2 (CB2), are embedded in cell membranes and act as the main targets for the system’s messengers. The presence of CB1 and CB2 is not universal, which raises questions about how other animals maintain physiological balance without these specific signaling tools.
Functions of Cannabinoid Receptors
The CB1 receptor is one of the most abundant G-protein coupled receptors found in the vertebrate brain and central nervous system. Its high concentration in areas like the cerebral cortex, cerebellum, and basal ganglia underlies its regulatory role in complex functions. CB1 activation regulates processes such as mood, memory, cognition, pain perception, and motor coordination. This receptor is responsible for a unique form of communication called retrograde signaling, where the receiving neuron releases endocannabinoids that travel backward across the synapse to the transmitting neuron.
In contrast, the CB2 receptor is primarily associated with immune function and peripheral tissues, with limited expression in the central nervous system. CB2 is heavily expressed on immune cells, including T cells, B cells, and macrophages. Activation of CB2 helps to modulate the immune response, cytokine release, and inflammatory pathways. Both receptor types are integral to maintaining internal equilibrium in the organisms that possess them.
Animals That Lack CB1 and CB2 Receptors
The canonical cannabinoid receptors, CB1 and CB2, are largely restricted to the phylum Chordata, meaning they are present in all vertebrates, including fish, birds, reptiles, and mammals. The animal groups that lack these specific receptors are primarily found within the domain of invertebrates, specifically the protostomes. Genomic analysis of these organisms shows no clear gene orthologs for the CB1 or CB2 receptors found in vertebrates.
A prominent group lacking the canonical receptors is the phylum Arthropoda, which includes all insects, crustaceans, and arachnids. Insects, such as the fruit fly (Drosophila melanogaster) and various species of bees, are devoid of the specific CB1/CB2 receptor system. Similarly, Nematodes, or roundworms, exemplified by the model organism Caenorhabditis elegans, do not possess CB1 or CB2 receptors in their genetic code.
Even in more primitive animals, the receptors are absent, though components of the system exist. Cnidarians, such as Hydra, possess the enzymatic machinery to produce endocannabinoid-like molecules, but lack verified CB1 or CB2 genes. These animals often retain the capacity to synthesize the endocannabinoid signaling molecules like anandamide and 2-arachidonoylglycerol.
Evolutionary Origins and Analogous Systems
The evolutionary history suggests that the gene for the CB1/CB2-type receptor originated in an ancient ancestor of the chordates, likely a deuterostomian invertebrate. This timing indicates that the full, integrated CB1/CB2 system is a feature that arose relatively late in animal evolution. Prior to this development, the components that make up the ECS were already present in much older lineages.
The ability to synthesize the signaling lipids, or endocannabinoids, is an ancient trait, dating back to the common ancestor of animals and plants. Even in animals that lack the receptors, such as insects, the enzymes responsible for creating and breaking down endocannabinoids are still active. This means the molecules are present, but they must interact with different receptor targets to exert their effects.
These non-CB1/CB2 mechanisms are referred to as analogous systems, which use the same signaling molecules but different protein targets to regulate cellular processes. For instance, in organisms like the leech, the endocannabinoid 2-AG acts by activating presynaptic transient receptor potential vanilloid-type (TRPV) ion channels. This alternative signaling pathway allows for endocannabinoid-mediated regulation of neural activity and other functions, demonstrating a functional replacement for the canonical receptors.