The History of CB2
The endocannabinoid receptor 2 (CB2) was discovered, characterized, and cloned by a research team at the MRC Laboratory of Molecular Biology, Cambridge, UK (S. Munro et al., 1993).1
CB2 General Expression and Distribution
In their initial finding, the researchers discovered CB2 in cells of the immune system, i.e., in macrophages and the marginal zone of the spleen. Subsequent research also found CB2 receptors in natural killer cells (e.g., B-cells) and densely expressed in the tonsils (S. Galiègue et al., 1995).2
While initially, it was believed CB2 was solely expressed in the periphery and cells of the immune system, subsequent research corrected the initial assumption after finding functional CB2 receptor sites and their gene transcripts described in various portions of the brain (E. Onaivi et al., 2006)3 including on the brain stem (M. Van Sickle et al., 2005).4
CB2 Distribution in the Human Brain
More specifically, a research team from the National Institute of Health describes the presence of CB2 in the olfactory tubercle, islands of Calleja, cerebral cortex, striatum, thalamic nuclei, hippocampus, amygdala, substantia nigra, periaqueductal gray, paratrochlear nucleus, paralemniscal nucleus, red nucleus, pontine nuclei, inferior colliculus and the parvocellular portion of the medial vestibular nucleus (Jian-Ping Gong et al., 2006).5
Recent evidence also discovered that CB2 receptors are present in brain dopamine neurons and microglia contributing to the so-called “tetrad” effects associated with the use of cannabis (i.e., hypomobility, hypothermia, analgesia, and catalepsy) (Q. R. Liu et al., 2020).6
The official name for the gene that codes for CB2 is CNR2 (National Library of Medicine, 2023).7
CB2 is a member of the guanine-nucleotide-binding protein (G-protein) coupled receptor family (S. Galiègue et al., 1995).8
Synthetic CB2 agonists
Researchers tested 18 CB2 agonists and found that the synthetic cannabinoids HU308, HU910, and JWH133 were the most selective for human CB2 receptors (M. Soethoudt et al., 2017).9
1. Munro S, Thomas KL, Abu-Shaar M. (1993 Sep). Molecular characterization of a peripheral receptor for cannabinoids. Nature. 365(6441):61-5.
2. Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P. (1995 Aug). Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 232(1):54-61.
3. Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, Meozzi PA, Myers L, Mora Z, Tagliaferro P, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Iwasaki S, Arinami T, Teasenfitz L, Uhl GR. (2006 Aug) Discovery of the presence and functional expression of cannabinoid CB2 receptors in the brain. Ann N Y Acad Sci. 1074:514-36.
4. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA. (2005 Oct) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 310(5746):329-32.
5. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR. (2006 Feb) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 1071(1):10-23.
6. Liu, Q. R., Canseco-Alba, A., Liang, Y., Ishiguro, H., & Onaivi, E. S. (2020). Low Basal CB2R in Dopamine Neurons and Microglia Influences Cannabinoid Tetrad Effects. International journal of molecular sciences, 21(24), 9763.
7. National Library of Medicine. Retrieved January 27, 2023. https://www.ncbi.nlm.nih.gov/gene/1269
8. Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P. (1995 Aug) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 232(1):54-61.
9. Soethoudt, M., Grether, U., Fingerle, J. et al. (2017) Cannabinoid CB2 receptor ligand profiling reveals biased signaling and off-target activity. Nat Commun 8, 13958.