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The Endocannabinoid System
The Endocannabinoid System
⬆️ retrograde neurotransmission of endocannabinoids in the nervous system, via CB1
O'dell, Chloe & Tuell, Dawn & Shah, Darshan & Stone, William. (2022). The systems medicine of cannabinoids in pediatrics: the case for more pediatric studies. Frontiers in Bioscience. 27. 1-14. 10.31083/j.fbl2701014.
Lu, H., & Mackie, K. (2016). An introduction to the endogenous cannabinoid system. Biological Psychiatry, 79(7), 516–525. https://doi.org/10.1016/j.biopsych.2015.07.028
Battista, N., Di Tommaso, M., Bari, M., & Maccarrone, M. (2012). The endocannabinoid system: an overview. Frontiers in Behavioral Neuroscience, 6. https://doi.org/10.3389/fnbeh.2012.00009
Castillo, P. E., Younts, T. J., Chávez, A. E., & Hashimotodani, Y. (2012). Endocannabinoid signaling and synaptic function. Neuron, 76(1), 70–81. https://doi.org/10.1016/j.neuron.2012.09.020
Simard, M., Archambault, A., Lavoie, J. C., Dumais, É., Di Marzo, V., & Flamand, N. (2022). Biosynthesis and metabolism of endocannabinoids and their congeners from the monoacylglycerol and N-acyl-ethanolamine families. Biochemical Pharmacology, 205, 115261. https://doi.org/10.1016/j.bcp.2022.115261
⬅️ biosynthetic pathway of the endogenous cannabinoid, anandamide.
Liu, J., Wang, L., Harvey‐White, J., Huang, B., Kim, H., Luquet, S., Palmiter, R. D., Krystal, G., Rai, R., Mahadevan, A., Razdan, R. K., & Kunos, G. (2008). Multiple pathways involved in the biosynthesis of anandamide. Neuropharmacology, 54(1), 1–7. https://doi.org/10.1016/j.neuropharm.2007.05.020
Baggelaar, M. P., Maccarrone, M., & Van Der Stelt, M. (2018). 2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain. Progress in Lipid Research, 71, 1–17. https://doi.org/10.1016/j.plipres.2018.05.002
Zhu, D., Zhang, J., Hashem, J., Gao, F., & Chen, C. (2023). Inhibition of 2-arachidonoylglycerol degradation enhances glial immunity by single-cell transcriptomic analysis. Journal of Neuroinflammation, 20(1). https://doi.org/10.1186/s12974-023-02701-4
⬅️ Table of the amount of endocannabinoids in both sperm and seminal plasma.
Lewis, S., Rapino, C., Di Tommaso, M., Pucci, M., Battista, N., Paro, R., Lee, S., Lutton, D., & Maccarrone, M. (2012). Differences in the Endocannabinoid System of Sperm from Fertile and Infertile Men. PloS One, 7(10), e47704. https://doi.org/10.1371/journal.pone.0047704
Effects on Memory
Hájos, N. (2021). Interneuron types and their circuits in the basolateral amygdala. Frontiers in Neural Circuits, 15. https://doi.org/10.3389/fncir.2021.687257
McDonald, A. J. (2020). Functional neuroanatomy of the basolateral amygdala: Neurons, neurotransmitters, and circuits. In Handbook of behavioral neuroscience (pp. 1–38). https://doi.org/10.1016/b978-0-12-815134-1.00001-5
Yang, Y., & Wang, J. (2017). From structure to behavior in basolateral Amygdala-Hippocampus circuits. Frontiers in Neural Circuits, 11. https://doi.org/10.3389/fncir.2017.00086
Atsak, P., Hauer, D., Campolongo, P., Schelling, G., Fornari, R. V., & Roozendaal, B. (2014). Endocannabinoid Signaling within the Basolateral Amygdala Integrates Multiple Stress Hormone Effects on Memory Consolidation. Neuropsychopharmacology, 40(6), 1485–1494. https://doi.org/10.1038/npp.2014.334
Ameri, A., Wilhelm, A., & Simmet, T. (1999). Effects of the endogeneous cannabinoid, anandamide, on neuronal activity in rat hippocampal slices. British Journal of Pharmacology, 126(8), 1831–1839. https://doi.org/10.1038/sj.bjp.0702478
⬅️ different neuronal circuits of the BLA and their associated functions.
Janak, P. H., & Tye, K. M. (2015). From circuits to behaviour in the amygdala. Nature, 517(7534), 284–292. https://doi.org/10.1038/nature14188
Amir, A., Kyriazi, P., Lee, S. C., Headley, D. B., & Paré, D. (2019). Basolateral amygdala neurons are activated during threat expectation. Journal of Neurophysiology, 121(5), 1761–1777. https://doi.org/10.1152/jn.00807.2018
⬅️ Anandamide's effects on glutamatergic and GABAergic neurons, with differential FAAAH expression.
Morena, M., Aukema, R. J., Leitl, K. D., Rashid, A. J., Vecchiarelli, H. A., Josselyn, S. A., & Hill, M. N. (2018). Upregulation of anandamide hydrolysis in the basolateral complex of amygdala reduces fear memory expression and indices of stress and anxiety. the Journal of Neuroscience/the Journal of Neuroscience, 39(7), 1275–1292. https://doi.org/10.1523/jneurosci.2251-18.2018
Effects on Anxiety/Stress
Hill, M. N., Patel, S., Campolongo, P., Tasker, J. G., Wotjak, C. T., & Bains, J. S. (2010). Functional Interactions between Stress and the Endocannabinoid System: From Synaptic Signaling to Behavioral Output. the Journal of Neuroscience/the Journal of Neuroscience, 30(45), 14980–14986. https://doi.org/10.1523/jneurosci.4283-10.2010
Riebe, C. J., & Wotjak, C. T. (2011). Endocannabinoids and stress. Stress, 14(4), 384–397. https://doi.org/10.3109/10253890.2011.586753
Morena, M., Patel, S., Bains, J. S., & Hill, M. N. (2015). Neurobiological interactions between stress and the endocannabinoid system. Neuropsychopharmacology, 41(1), 80–102. https://doi.org/10.1038/npp.2015.166
⬅️ effects of increased FAAH and therefore decreased AEA in the BLA during stress exposure.
Gunduz-Cinar, O., Hill, M. N., McEwen, B. S., & Holmes, A. (2013). Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends in Pharmacological Sciences, 34(11), 637–644. https://doi.org/10.1016/j.tips.2013.08.008
Gray, J. M., Vecchiarelli, H. A., Morena, M., Lee, T. T., Hermanson, D. J., Kim, A. B., McLaughlin, R. J., Hassan, K. I., Kühne, C., Wotjak, C. T., Deussing, J. M., Patel, S., & Hill, M. N. (2015). Corticotropin-Releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. the Journal of Neuroscience/the Journal of Neuroscience, 35(9), 3879–3892. https://doi.org/10.1523/jneurosci.2737-14.2015
Sample, I. (2019, March 28). Scientists find genetic mutation that makes woman feel no pain. The Guardian. https://www.theguardian.com/science/2019/mar/28/scientists-find-genetic-mutation-that-makes-woman-feel-no-pain
Habib, A. M., Okorokov, A. L., Hill, M. N., Brás, J., Lee, M. C., Li, S., Gossage, S. J., Van Drimmelen, M., Morena, M., Houlden, H., Ramirez, J. D., Bennett, D. L., Srivastava, D., & Cox, J. J. (2019). Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. British Journal of Anaesthesia, 123(2), e249–e253. https://doi.org/10.1016/j.bja.2019.02.019
Bluett, R. J., Gamble-George, J., Hermanson, D. J., Hartley, N. D., Marnett, L. J., & Patel, S. (2014). Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. Translational Psychiatry, 4(7), e408. https://doi.org/10.1038/tp.2014.53
Scherma, M., Masia, P., Satta, V., Fratta, W., Fadda, P., & Tanda, G. (2018). Brain activity of anandamide: a rewarding bliss? Acta Pharmacologica Sinica, 40(3), 309–323. https://doi.org/10.1038/s41401-018-0075-x
Effects on Feeding Behavior
⬆️ neurons in the hypothalamus that control satiety, and their associated neurostransmitters.
Vicent, Maria & Mook, Conor & Carter, Matthew. (2018). POMC neurons in heat: A link between warm temperatures and appetite suppression. PLOS Biology. 16. e2006188. 10.1371/journal.pbio.2006188.
Watkins, B. A., & Kim, J. (2015). The endocannabinoid system: directing eating behavior and macronutrient metabolism. Frontiers in Psychology, 5. https://doi.org/10.3389/fpsyg.2014.01506
Van Ackern, I., Kuhla, A., & Kuhla, B. (2021). A Role for Peripheral Anandamide and 2-Arachidonoylglycerol in Short-Term Food Intake and Orexigenic Hypothalamic Responses in a Species with Continuous Nutrient Delivery. Nutrients, 13(10), 3587. https://doi.org/10.3390/nu13103587
Jiang, H. (2022). Hypothalamic GABAergic neurocircuitry in the regulation of energy homeostasis and sleep/wake control. Medical Review, 2(5), 531–540. https://doi.org/10.1515/mr-2022-0022
⬅️ orexinergic signalling in the hypothalamus, mediated by CB1 receptors.
Flores, Á., Maldonado, R., & Berrendero, F. (2013). Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far. Frontiers in Neuroscience, 7. https://doi.org/10.3389/fnins.2013.00256
Schulz, P., Hryhorowicz, S., Rychter, A. M., Zawada, A., Słomski, R., Dobrowolska, A., & Krela‐Kaźmierczak, I. (2021). What role does the endocannabinoid system play in the pathogenesis of obesity? Nutrients, 13(2), 373. https://doi.org/10.3390/nu13020373
Effects on the GI Tract
⬅️ Summary of ECS interactions with various aspects of the GI tract, including the microbiome and the immune system.
Cuddihey, H., MacNaughton, W. K., & Sharkey, K. A. (2022). Role of the endocannabinoid system in the regulation of intestinal homeostasis. CMGH, 14(4), 947–963. https://doi.org/10.1016/j.jcmgh.2022.05.015
Moriello, A. S., Di Marzo, V., & Petrosino, S. (2022). Mutual Links between the Endocannabinoidome and the Gut Microbiome, with Special Reference to Companion Animals: A Nutritional Viewpoint. Animals, 12(3), 348. https://doi.org/10.3390/ani12030348
Srivastava, R. a. K., Lutz, B., & De Azúa, I. R. (2022). The microbiome and gut endocannabinoid system in the regulation of stress responses and metabolism. Frontiers in Cellular Neuroscience, 16. https://doi.org/10.3389/fncel.2022.867267
Runner's High
⬅️ mice still showed the tell-tale decrease in anxiety/pain sensitivity when opioids were blocked, but not when cannabinoids were blocked, suggesting that cannabinoids play a more significant role in the runner's high.
Fuß, J., Steinle, J., Bîndilă, L., Auer, M., Kirchherr, H., Lutz, B., & Gass, P. (2015). A runner’s high depends on cannabinoid receptors in mice. Proceedings of the National Academy of Sciences of the United States of America, 112(42), 13105–13108. https://doi.org/10.1073/pnas.1514996112
Winiarz, E., Winiarz. (2019). Endorphins, endocannabinoids and runners’ high. In The Science Journal of the Lander College of Arts and Sciences (No. 1; Vol. 13). https://touroscholar.touro.edu/cgi/viewcontent.cgi?article=1229&context=sjlcas
Siebers, M., Biedermann, S. V., Bîndilă, L., Lutz, B., & Fuß, J. (2021). Exercise-induced euphoria and anxiolysis do not depend on endogenous opioids in humans. Psychoneuroendocrinology, 126, 105173. https://doi.org/10.1016/j.psyneuen.2021.105173
⬅️ Amyloid fibril of B-endorphin, the molecule we once thought controlled exercise-induced euphoria.
Bank, R. P. D. (n.d.). RCSB PDB - 6TUB: Beta-endorphin amyloid fibril. https://www.rcsb.org/structure/6tub
Cannabinoids
Cannabinoids
Sheikh, N. K., & Dua, A. (2023, February 27). Cannabinoids. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK556062/
Chayasirisobhon, S. (2021). Mechanisms of action and pharmacokinetics of cannabis. the Permanente Journal/Permanente Journal, 25(1), 1–3. https://doi.org/10.7812/tpp/19.200
⬅️ anti-inflammatory effect mediated by CBD via NF-kB suppression.
Naya, N. M., Kelly, J., Corna, G., Golino, M., Abbate, A., & Toldo, S. (2023). Molecular and cellular mechanisms of action of cannabidiol. Molecules/Molecules Online/Molecules Annual, 28(16), 5980. https://doi.org/10.3390/molecules28165980
Cannabinoid Receptors
Cannabinoid Receptors
Receptor Basics
⬅️ amino acid sequence of the two main cannabinoid receptors.
Reggio, P. H. (2010). Endocannabinoid binding to the cannabinoid receptors: What is known and what remains unknown. Current Medicinal Chemistry, 17(14), 1468–1486. https://doi.org/10.2174/092986710790980005
Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid receptors in the central nervous system: their signaling and roles in disease. Frontiers in Cellular Neuroscience, 10. https://doi.org/10.3389/fncel.2016.00294
Mackie, K., J., Lai, Y., Westenbroek, R., R. Mitchell, Departments of Anesthesiology and Physiology and Biophysics, University of Washington, Panlabs, & Department of Pharmacology, University of Washington. (1995). Cannabinoids Activate an Inwardly Rectifying Potassium Conductance and Inhibit Q-Type Calcium Currents in AtT20 Cells Transfected with Rat Brain Cannabinoid Receptor. In The Journal of Neuroscience (Vol. 10, pp. 6552–6561). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6578016/pdf/jneuro_15_10_6552.pdf
Lin, Y. (2021). Potassium channels as molecular targets of endocannabinoids. Channels, 15(1), 408–423. https://doi.org/10.1080/19336950.2021.1910461
⬅️ Table of binding affinities for some endocannabinoids/cannabinoids at human and rat cannabinoid receptors. The lower the Ki, the higher the affinity.
McPartland, J., Glass, M., & Pertwee, R. G. (2007). Meta‐analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. British Journal of Pharmacology, 152(5), 583–593. https://doi.org/10.1038/sj.bjp.0707399
Pertwee, R. G., Howlett, A. C., Abood, M. E., Alexander, S. P., Di Marzo, V., Elphick, M. R., Greasley, P. J., Hansen, H. S., Kunos, G., Mackie, K., Mechoulam, R., & Ross, R. A. (2010). International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: Beyond CB1and CB2. Pharmacological Reviews, 62(4), 588–631. https://doi.org/10.1124/pr.110.003004
CB1 Brain and Peripheral Expression
CNR1 protein expression summary - The Human Protein Atlas. (n.d.). https://www.proteinatlas.org/ENSG00000118432-CNR1
Turu, G., & Hunyady, L. (2009). Signal transduction of the CB1 cannabinoid receptor. Journal of Molecular Endocrinology, 44(2), 75–85. https://doi.org/10.1677/jme-08-0190
Howlett, A. C., Blume, L. C., & Dalton, G. D. (2010). CB1 Cannabinoid Receptors and their Associated Proteins. Current Medicinal Chemistry, 17(14), 1382–1393. https://doi.org/10.2174/092986710790980023
Katona, I., Rancz, E. A., Acsády, L., Ledent, C., Mackie, K., Hájos, N., & Freund, T. F. (2001). Distribution of CB1 Cannabinoid Receptors in the Amygdala and their Role in the Control of GABAergic Transmission. the Journal of Neuroscience/the Journal of Neuroscience, 21(23), 9506–9518. https://doi.org/10.1523/jneurosci.21-23-09506.2001
Zagzoog, A., Cabecinha, A., Abramovici, H., & Laprairie, R. B. (2022). Modulation of type 1 cannabinoid receptor activity by cannabinoid by-products from Cannabis sativa and non-cannabis phytomolecules. Frontiers in Pharmacology, 13. https://doi.org/10.3389/fphar.2022.956030
CB2 Brain and Peripheral Expression
CNR2 protein expression summary - The Human Protein Atlas. (n.d.). https://www.proteinatlas.org/ENSG00000188822-CNR2
⬅️ CB2 expression is particularly dense in certain immune cells. Especially B-cells.
Rahaman, O., & Ganguly, D. (2021). Endocannabinoids in immune regulation and immunopathologies. Immunology, 164(2), 242–252. https://doi.org/10.1111/imm.13378
Sido, J. M., Nagarkatti, P., & Nagarkatti, M. (2016). Production of endocannabinoids by activated T cells and B cells modulates inflammation associated with delayed‐type hypersensitivity. European Journal of Immunology, 46(6), 1472–1479. https://doi.org/10.1002/eji.201546181
Rojo-Bustamante, E., Íñigo-Marco, I., Abellanas, M. A., Vinueza-Gavilanes, R., Baltanás, A., Luquin, E., Arrasate, M., & Aymerich, M. S. (2020). CB2 receptors and Neuron–GliA interactions modulate neurotoxicity generated by MAGL inhibition. Biomolecules, 10(8), 1198. https://doi.org/10.3390/biom10081198
Komorowska-Müller, J. A., & Schmöle, A. (2020). CB2 receptor in microglia: The Guardian of Self-Control. International Journal of Molecular Sciences, 22(1), 19. https://doi.org/10.3390/ijms22010019
⬅️ Endocannabinoids and synthetic cannabinoids interact with CB receptors on glial cells to modulate inflammatory cytokines.
Egaña‐Huguet, J., Soria‐Gómez, E., & Grandes, P. (2021). The Endocannabinoid System in Glial Cells and Their Profitable Interactions to Treat Epilepsy: Evidence from Animal Models. International Journal of Molecular Sciences, 22(24), 13231. https://doi.org/10.3390/ijms222413231
Muppidi, J. R., Arnon, T. I., Bronevetsky, Y., Veerapen, N., Tanaka, M., Besra, G. S., & Cyster, J. G. (2011). Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone. the Journal of Experimental Medicine/the Journal of Experimental Medicine, 208(10), 1941–1948. https://doi.org/10.1084/jem.20111083
Strisciuglio, C., Creoli, M., Tortora, C., Martinelli, M., Miele, E., Paino, S., Luongo, L., & Rossi, F. (2022). Increased expression of CB2 receptor in the intestinal biopsies of children with inflammatory bowel disease. Pediatric Research, 93(3), 520–525. https://doi.org/10.1038/s41390-022-02109-5
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