Quick answer
Two cannabinoid receptors are cloned and confirmed: CB1 and CB2. Both are G protein-coupled receptors. THC binds both. CB1 is concentrated in the brain, spinal cord, and peripheral nerves. CB2 sits on immune cells. Other proteins bind cannabinoids, including GPR55, TRPV1, PPARα, and 5-HT1A, but most researchers do not classify them as cannabinoid receptors under the strict definition.
Role of CB1 and CB2 Receptors in Cannabis
CB1 receptors
CB1 was cloned in 1990. The gene is CNR1, on chromosome 6. Counts are high in the cerebellum, hippocampus, basal ganglia, and cortex. Counts are low in the brainstem, which is part of the reason cannabis does not suppress breathing the way opioids do. CB1 also appears in liver, fat tissue, gut, and reproductive organs.
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CB1 couples to Gi/o proteins. Activation lowers cyclic AMP, opens potassium channels, and closes calcium channels. The result is less neurotransmitter release at the synapse.
what do cannabinoid receptors do
CB2 receptors
CB2 was cloned in 1993. The gene is CNR2. CB2 is found on B cells, T cells, macrophages, and microglia. Levels in the brain are low under normal conditions. Levels rise with inflammation or injury.
what do cannabinoid receptors do
Endocannabinoids
The body makes two main endocannabinoids: anandamide (AEA) and 2-arachidonoylglycerol (2-AG). 2-AG is a full agonist at both receptors. Anandamide is a partial agonist with higher affinity for CB1. The enzymes FAAH and MAGL break them down after use.
How THC and CBD act
THC is a partial agonist at CB1 and CB2. The psychoactive effects track to CB1. CBD has low affinity for both receptors. CBD acts as a negative allosteric modulator at CB1, and as an inverse agonist at CB2 in some assays. CBD also inhibits FAAH, which slows anandamide breakdown.
Other targets
- GPR55: an orphan receptor. Some researchers call it CB3. Cannabinoids bind it, but the label is still debated.
- TRPV1: a capsaicin receptor. CBD and anandamide activate it. It handles pain and temperature sensing.
- PPARα: a nuclear receptor. Some cannabinoids activate it and shift lipid metabolism.
- 5-HT1A: a serotonin receptor. CBD binds it as an agonist.
Why the split matters
CB1 and CB2 differ in tissue location, gene sequence, and drug response. That split drives drug design. Researchers look for CB1 antagonists for metabolic work and CB2 agonists for inflammation work, with the goal of hitting one receptor without the other.
Key numbers
- CB1 cloned: 1990
- CB2 cloned: 1993
- Receptors classified as cannabinoid receptors: 2
- Main endocannabinoids: 2 (anandamide, 2-AG)