It was initially thought that cannabinoids acted on non-specific membrane-associated receptors. Then there was the discovery of the cannabinoid 1 receptor (CB1) in the brain and central nervous system.7 The endocannabinoid anandamide (AEA) and the phytocannabinoid tetrahydrocannabinol (THC) activate CB1 receptors.
A second cannabinoid-specific G-protein type receptor, cannabinoid receptor 2 (CB2) was later discovered in the peripheral nervous system. This discovery demonstrated to researchers and the world that the body has an innate endocannabinoid system with specific cellular binding sites.
A cell’s membrane is like it’s skin. It contains sensors and structures like protein receptors and ion channels that it uses to interact with the rest of the body. Signal molecules can interact with protein receptors on the cell and bring the cell messages. This is how the body can alter cell activity to get cells to respond to a stimulus.
Signal molecules like cannabinoids are scientifically are known as ligands. Native ligands like endocannabinoids are naturally produced by the body. However, ligands can also come from sources outside the body that closely mimic the natural ligands. This is the case for phytocannabinoids (plant-derived) like the cannabis-derived cannabinoids THC and CBD.
The Endocannabinoid System and CB1 Receptors
CB1 receptors are expressed on the nerve axon terminals of central and peripheral neurons.6 In this location, the cannabinoid 1 receptor regulates the release of various neurotransmitters. Some major neurotransmitters regulated by the cannabinoid 1 receptor include acetylcholine, norepinephrine, dopamine, 5-hydroxytryptamine, glutamate, and GABA. These neurotransmitters play significant roles in diseases and disorders like anxiety, depression, chronic pain, and multiple sclerosis (MS), along with neurodegenerative conditions.
The activity of the endocannabinoid system in the central nervous system attributed to the high abundance of CB1 receptors in the brain’s hippocampus and amygdala.6 The hippocampus is responsible for short-term memory. The amygdala is responsible for fear-memories, pain, and emotional control.
The presence of CB1 receptors in those brain sites has been correlated to the effects of CB1-binding substances like THC.6 CB1 receptors are notably absent from the brainstem. This is thought to be the reason why no fatality has been recorded from the over-consumption of marijuana.
Effects of THC Correlated to CB1
- Psychoactivity (intoxication)
- Altered motor function
- Inhibition of some types of memory
Initially, it was thought that CB1 receptors existed only in the central nervous system.7 Surprisingly, the cannabinoid 1 receptor protein has also been found in lower concentrations in the peripheral nervous system. In the peripheral nervous system, the endocannabinoid system expresses CB1 receptors in fat cells (adipocytes), the liver, the pancreas, in skeletal muscle, and non-neuron immune cells.6
What are CB1 Receptors?
The CB1 receptor is a G protein-coupled cannabinoid receptor that in humans is encoded by the CNR1 gene.1.G protein-coupled receptors (GPCRs) are a family of large protein receptors that detect molecules outside the cell and activate internal signal transduction pathways.8
These signal transduction pathways carry signals from neurons to sites of action where they produce cellular responses. The cAMP signal pathway and the phosphatidylinositol signal pathway are the two principal signal transduction pathways involving the G protein-coupled receptors.3
When a ligand like a cannabinoid binds to the GPCR, it causes it to change shape and undergo further processes that lead to the alteration in signaling between cells.4 G protein-coupled receptors like CB1 are so crucial to the way our bodies function that about 34% of FDA approved drugs use them as a target mechanism.
The Importance of Cannabinoid 1 Receptor
CB1 receptors are present from the early stages of embryonic development and remain with us through life.7 Throughout aging and development, the abundance and sensitivity of CB1 receptors changes. In early life, the presence of CB1 receptors is essential. Surprisingly, even newborns have cannabinoid receptors.
As the body ages, the CB1 receptors that are abundant in the white matter of the newborn brain decrease in concentration. Because of this, children and adolescents can often get more cannabinoid benefits at lower doses, but adults may need higher doses to get the same effects.
The cannabinoid 1 receptor plays many vital roles in the endocannabinoid system and can play a significant role in how well out bodies function. The most fundamental role of the CB1 receptor is to down-regulate neurotransmitters by inhibiting common neurotransmitter channels involving signals from potassium and calcium. The inhibition of these neurotransmitter channels is what leads to the sedative effects of marijuana.6
The CB1 receptor has been implicated in neuronal growth, brain plasticity, and cell migration.7 These CB1-related functions are attributed to a decrease in cyclic adenosine monophosphate (cAMP) accumulation and hence to inhibition of cAMP-dependent protein kinase (PKA) by CB1 activation.
More broadly, CB1 activity can help promote homeostasis and balance in the body. It has known links to the reduction of pain and inflammation. As a result, CB1 receptors are also a target as a new approach to combating addiction.2 CB1 has a link to motivational circuits and plays a role in how CBD affects the brain. There is growing evidence that activation of CB1 may inhibit drug relapse and addiction behaviors with substances like nicotine, alcohol, and opiates.
Cannabinoid 1 Receptor: Final Thoughts
The cannabinoid 1 receptor is one of the principal receptors of the endocannabinoid system. Therefore, people can feel high and sedated when THC activates CB1, but activation of CB1 unlocks many health benefits as well.5 The physiological potential of the endocannabinoid system is realized through cannabinoid receptors like CB1. Potential benefits include analgesic effects, inflammation reduction, addiction recovery support, and proper childhood brain development.
- Abood M, Barth F, Bonner TI, Cabral G, Casellas P, Cravatt BF, Devane WA, Elphick MR, Felder CC, Herkenham M, Howlett AC, Kunos G, Mackie K, Mechoulam R, Pertwee RG (22 August 2018). “CB1 Receptor”. IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology.
- De Vries TJ, Schoffelmeer AN (August 2005). “Cannabinoid CB1 receptors control conditioned drug seeking”. Trends in Pharmacological Sciences. 26 (8): 420–6. doi:10.1016/j.tips.2005.06.00. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/15992935
- Gilman AG (1987). “G proteins: transducers of receptor-generated signals.” Annual Review of Biochemistry. 56 (1): 615–49. doi:10.1146/annurev.bi.56.070187.003151. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/3113327
- Hauser AS, Chavali S, Masuho I, Jahn LJ, Martemyanov KA, Gloriam DE, Babu MM (January 2018). “Pharmacogenomics of GPCR Drug Targets.” Cell. 172 (1–2): 41–54.e19. doi:10.1016/j.cell.2017.11.033. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766829/
- Katona, I., & Freund, T. F. (2012). Multiple functions of endocannabinoid signaling in the brain. Annual review of neuroscience, 35, 529-558. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273654/?report=classic
- Kaur, R., R Ambwani, S., & Singh, S. (2016). Endocannabinoid system: a multi-facet therapeutic target. Current clinical pharmacology, 11(2), 110-117. Retrieved from: https://www.researchgate.net/profile/Sneha_Ambwani/publication/301533431_Endocannabinoid_System_A_Multi-Facet_Therapeutic_Target/links/5a544667a6fdccf3e2e29f74/Endocannabinoid-System-A-Multi-Facet-Therapeutic-Target.pdf
- Mechoulam, R., & Parker, L. A. (2013). The endocannabinoid system and the brain. Annual review of psychology, 64, 21-47. Retrieved from: https://www.researchgate.net/profile/Raphael_Mechoulam2/publication/229163258_The_Endocannabinoid_System_and_the_Brain/links/5469dae80cf2f5eb18054fc8/The-Endocannabinoid-System-and-the-Brain.pdf
- Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S (2012). “Action of molecular switches in GPCRs—theoretical and experimental studies.” Current Medicinal Chemistry. 19 (8): 1090–109. doi:10.2174/092986712799320556. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343417/