Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-cd9895bd7-dzt6s Total loading time: 0 Render date: 2024-12-18T02:27:04.519Z Has data issue: false hasContentIssue false

Chapter 2 - The Function of the Endocannabinoid System

from Part I - Pharmacology of Cannabis and the Endocannabinoid System

Published online by Cambridge University Press:  12 May 2023

By
Nathan D. Winters  and
Sachin Patel
Edited by
Deepak Cyril D'Souza ,
David Castle  and
Sir Robin Murray
Deepak Cyril D'Souza
Affiliation:
Staff Psychiatrist, VA Connecticut Healthcare System; Professor of Psychiatry, Yale University School of Medicine
David Castle
Affiliation:
University of Tasmania, Australia
Sir Robin Murray
Affiliation:
Honorary Consultant Psychiatrist, Psychosis Service at the South London and Maudsley NHS Trust; Professor of Psychiatric Research at the Institute of Psychiatry
Get access

Summary

The endocannabinoid system is a lipid-derived, retrograde neuromodulatory system with widespread functions in the central nervous system, among other tissues. Initially discovered through research efforts directed at identifying the biological target of Cannabis¬-derived cannabinoids, the endocannabinoid system has been demonstrated to play critical roles in synaptic transmission and the regulation of myriad aspects of nervous system physiology and behaviour, such as anxiety, pain, and sleep. Comprised of the endocannabinoid ligands, the enzymes responsible for their synthesis and degradation, and the cannabinoid receptors, the endocannabinoid system has been the topic of a rapidly expanding field of research in both the basic sciences and drug development. Herein we describe the history, function and recent developments in our understanding of this complex neuromodulatory signalling system.

Keywords

endocannabinoidscannabinoid receptors2-arachidonoylglycerolanandamide
Type
Chapter
Information
Marijuana and Madness , pp. 12 - 20
Publisher: Cambridge University Press
Print publication year: 2023

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Acuna-Goycolea, C., Obrietan, K., and Van Den Pol, A. N. (2010). Cannabinoids excite circadian clock neurons. J Neurosci, 30, 10061–10066.Google Scholar
Agarwal, N., Pacher, P., Tegeder, I., et al. (2007). Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci, 10, 870–879.Google Scholar
Bakas, T., van Nieuwenhuijzen, P. S., Devenish, S. O., et al. (2017). The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacol Res, 119, 358–370.Google Scholar
Bedse, G., Hartley, N. D., Neale, E., et al. (2017). Functional redundancy between canonical endocannabinoid signaling systems in the modulation of anxiety. Biol Psychiatry, 82, 488–499.Google Scholar
Bedse, G., Hill, M. N., and Patel, S. (2020). 2-Arachidonoylglycerol modulation of anxiety and stress adaptation: From grass roots to novel therapeutics. Biol Psychiatry, 88, 520–530.Google Scholar
Bénard, G., Massa, F., Puente, N., et al. (2012). Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat Neurosci, 15, 558–564.Google Scholar
Blázquez, C., Chiarlone, A., Bellocchio, L., et al. (2015). The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. Cell Death Differ, 22, 1618–1629.Google Scholar
Bluett, R. J., Báldi, R., Haymer, A., et al. (2017). Endocannabinoid signalling modulates susceptibility to traumatic stress exposure. Nat Commun, 8, 14782.Google Scholar
Bonn-Miller, M. O., Boden, M. T., Bucossi, M. M., et al. (2014). Self-reported cannabis use characteristics, patterns and helpfulness among medical cannabis users. Am J Drug Alcohol Abuse, 40, 23–30.Google Scholar
den Boon, F. S., Chameau, P., Schaafsma-Zhao, Q., et al. (2012). Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors. Proc Natl Acad Sci USA, 109, 3534–3539.CrossRefGoogle ScholarPubMed
Carriba, P., Ortiz, O., Patkar, K., et al. (2007). Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacology, 32, 2249–2259.Google Scholar
Cascio, M. G., and Marini, P. (2015). Biosynthesis and fate of endocannabinoids. Handb Exp Pharmacol, 231, 39–58.Google Scholar
Congreve, M., de Graaf, C., Swain, N. A., et al. (2020). Impact of GPCR structures on drug discovery. Cell, 181, 81–91.Google Scholar
Covelo, A., Eraso-Pichot, A., Fernández-Moncada, I., et al. (2021). CB1R-dependent regulation of astrocyte physiology and astrocyte-neuron interactions. Neuropharmacology, 195, 108678.Google Scholar
Covey, D. P., Mateo, Y., Sulzer, D., et al. (2017). Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology, 124, 52–61.Google Scholar
Devane, W. A., Dysarz, F. A., Johnson, M. R., et al. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol, 34, 605–613.Google Scholar
Eldeeb, K., Leone-Kabler, S., and Howlett, A. C. (2016). CB1 cannabinoid receptor-mediated increases in cyclic AMP accumulation are correlated with reduced Gi/o function. J Basic Clin Physiol Pharmacol, 27, 311–322.CrossRefGoogle ScholarPubMed
Feinberg, I., Jones, R., Walker, J., et al. (1976). Effects of marijuana extract and tetrahydrocannabinol on electroencephalographic sleep patterns. Clin Pharmacol Ther, 19, 782–794.Google Scholar
Finlay, D. B., Cawston, E. E., Grimsey, N. L., et al. (2017). Gαs signalling of the CB1 receptor and the influence of receptor number. Br J Pharmacol, 174, 2545–2562.Google Scholar
Finn, D. P., Haroutounian, S., Hohmann, A. G., et al. (2021). Cannabinoids, the endocannabinoid system, and pain: A review of preclinical studies. Pain, 162, S5–25.Google Scholar
Gantz, S. C., and Bean, B. P. (2017). Cell-autonomous excitation of midbrain dopamine neurons by endocannabinoid-dependent lipid signaling. Neuron, 93, 1375–1387.Google Scholar
Gaoni, Y., and Mechoulam, R. (1964). Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc, 86, 1646–1647.Google Scholar
Garcia-Ovejero, D., Arevalo-Martin, A., Petrosino, S., et al. (2009). The endocannabinoid system is modulated in response to spinal cord injury in rats. Neurobiol Dis, 33, 57–71.Google Scholar
Guindon, J., and Beaulieu, P. (2006). Antihyperalgesic effects of local injections of anandamide, ibuprofen, rofecoxib and their combinations in a model of neuropathic pain, Neuropharmacology, 50, 814–823.Google Scholar
Guindon, J., Desroches, J., and Beaulieu, P. (2007). The antinociceptive effects of intraplantar injections of 2-arachidonoyl glycerol are mediated by cannabinoid CB 2 receptors. Br J Pharmacol, 150, 693–701.Google Scholar
Guindon, J., and Hohmann, A. (2009) The endocannabinoid system and pain. CNS Neurol Disord – Drug Targets, 8, 403–421.Google Scholar
Hablitz, L. M., Gunesch, A. N., Cravetchi, O., et al. (2020). Cannabinoid signaling recruits astrocytes to modulate presynaptic function in the suprachiasmatic nucleus. eNeuro, 7, ENEURO.0081-19.2020.Google Scholar
Haj-Dahmane, S., Shen, R. Y., Elmes, M. W., et al. (2018) Fatty-acid-binding protein 5 controls retrograde endocannabinoid signaling at central glutamate synapses. Proc Natl Acad Sci USA, 115, 3482–3487.Google Scholar
Haspula, D., and Clark, M. A. (2020) Cannabinoid receptors: An update on cell signaling, pathophysiological roles and therapeutic opportunities in neurological, cardiovascular, and inflammatory diseases. Int J Mol Sci, 21, 7693.Google Scholar
Hebert-Chatelain, E., Desprez, T., Serrat, R., et al. (2016) A cannabinoid link between mitochondria and memory. Nature, 539, 555–559.Google Scholar
Hill, M. N., Campolongo, P., Yehuda, R., et al. (2017). Integrating endocannabinoid signaling and cannabinoids into the biology and treatment of posttraumatic stress disorder. Neuropsychopharmacology, 43, 80–102.Google Scholar
Hill, M. N., and McEwen, B. S. (2010). Involvement of the endocannabinoid system in the neurobehavioural effects of stress and glucocorticoids. Prog Neuro-Psychopharmacology Biol Psychiatry, 34, 791–797.Google Scholar
Hill, M. N., McLaughlin, R. J., Bingham, B., et al. (2010). Endogenous cannabinoid signaling is essential for stress adaptation. Proc Natl Acad Sci USA, 107, 9406–9411.Google Scholar
Hojo, M., Sudo, Y., Ando, Y., et al. (2008). μ-Opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: Electrophysiological and fret assay analysis. J Pharmacol Sci, 108, 308–319.Google Scholar
Howlett, A. C., and Fleming, R. M. (1984). Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membrane. Mol Pharmacol, 26, 532–538.Google Scholar
Howlett, A. C., Qualy, J. M., and Khachatrian, L. L. (1986). Involvement of G(i) in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol Pharmacol, 29, 307–313.Google Scholar
Hua, T., Li, X., Wu, L., et al. (2020). Activation and signaling mechanism revealed by cannabinoid receptor-Gi complex structures. Cell, 180, 655–665.Google Scholar
Hua, T., Vemuri, K., Nikas, S. P., et al. (2017). Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature, 547, 468–471.Google Scholar
Hua, T., Vemuri, K., Pu, M., et al. (2016). Crystal structure of the human cannabinoid receptor CB1. Cell, 167, 750–762.Google Scholar
Ibeas Bih, C., Chen, T., Nunn, A. V., et al. (2015). Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics, 12, 699–730.CrossRefGoogle ScholarPubMed
Kesner, A. J., and Lovinger, D. M. (2020). Cannabinoids, endocannabinoids and sleep. Front Mol Neurosci, 13, 125.Google Scholar
Khan, S. S., and Lee, F. J. S. (2014). Delineation of domains within the cannabinoid CB1 and dopamine D2 receptors that mediate the formation of the heterodimer complex. J Mol Neurosci, 53, 10–21.Google Scholar
Kruk-Slomka, M., Dzik, A., Budzynska, B., et al. (2017). Endocannabinoid system: The direct and indirect involvement in the memory and learning processes – A short review. Mol Neurobiol, 54, 8332–8347.Google Scholar
Laprairie, R. B., Bagher, A. M., Kelly, M. E., et al. (2015). Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol, 172, 4790–4805.Google Scholar
Lauckner, J. E., Hille, B., and Mackie, K. (2005). The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc Natl Acad Sci USA, 102, 19144–19149.Google Scholar
Lauckner, J. E., Jensen, J. B., Chen, H.-Y., et al. (2008). GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci USA, 105, 2699–2704.Google Scholar
Lawrence, D. K., and Gill, E. W. (1975). The effects of Δ1 tetrahydrocannabinol and other cannabinoids on spin labeled liposomes and their relationship to mechanisms of general anesthesia. Mol Pharmacol, 11, 595–602.Google Scholar
Li, X., Hua, T., Vemuri, K., et al. (2019). Crystal structure of the human cannabinoid receptor CB2. Cell, 176, 459–467.Google Scholar
Marcus, D. J., Bedse, G., Gaulden, A. D., et al. (2020). Endocannabinoid signaling collapse mediates stress-induced amygdalo-cortical strengthening. Neuron, 105, 1062–1076.e6.Google Scholar
Martin-Fernandez, M., Jamison, S., Robin, L. M., et al. (2017). Synapse-specific astrocyte gating of amygdala-related behavior. Nat Neurosci, 20, 1540–1548.Google Scholar
Matsuda, L. A., Lolait, S. J., Brownstein, M. J., et al. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 346, 561–564.Google Scholar
Mechoulam, R., Lander, N., Srebnik, M., et al. (1980). Stereochemical requirements for cannabinoid activity. J Med Chem, 23, 1068–1072.Google Scholar
Mechoulam, R., and Shvo, Y. (1963). Hashish-I. The structure of cannabidiol. Tetrahedron, 19, 2073–2078.Google Scholar
Mendizabal-Zubiaga, J., Melser, S., Bénard, G., et al. (2016). Cannabinoid CB1 receptors are localized in striated muscle mitochondria and regulate mitochondrial respiration. Front Physiol, 7, 476.Google Scholar
Moreno, E., Chiarlone, A., Medrano, M., et al. (2018). Singular location and signaling profile of adenosine A2A-cannabinoid CB1 receptor heteromers in the dorsal striatum. Neuropsychopharmacology, 43, 964–977.Google Scholar
Navarrete, M., and Araque, A. (2008). Endocannabinoids mediate neuron-astrocyte communication. Neuron, 57, 883–893.CrossRefGoogle ScholarPubMed
Navarrete, M., and Araque, A. (2010). Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. Neuron, 68, 113–126.Google Scholar
Niehaus, J. L., Liu, Y., Wallis, K. T., et al. (2007). CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor interacting protein CRIP 1a. Mol Pharmacol, 72, 1557–1566.Google Scholar
Nogueras-Ortiz, C., and Yudowski, G. A. (2016). The multiple waves of cannabinoid 1 receptor signaling. Mol Pharmacol, 90, 620–626.Google Scholar
Nyilas, R., Gregg, L. C., Mackie, K., et al. (2009). Molecular architecture of endocannabinoid signaling at nociceptive synapses mediating analgesia. Eur J Neurosci, 29, 1964–1978.Google Scholar
O’Sullivan, S. E. (2007). Cannabinoids go nuclear: Evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol, 152, 576–582.Google Scholar
Ohno-Shosaku, T., Hashimotodani, Y., Ano, M., et al. (2007). Endocannabinoid signalling triggered by NMDA receptor-mediated calcium entry into rat hippocampal neurons. J Physiol, 584, 407–418.Google Scholar
Oubraim, S., Wang, R., Hausknecht, K. A., et al. (2021). Tonic endocannabinoid signaling gates synaptic plasticity in dorsal raphe nucleus serotonin neurons through peroxisome proliferator-activated receptors. Front Pharmacol, 12, 1–14.Google Scholar
Palazzo, E., Luongo, L., Novellis, V., et al. (2010). The role of cannabinoid receptors in the descending modulation of pain. Pharmaceuticals, 3, 2661–2673.Google Scholar
Parsons, L. H., and Hurd, Y. L. (2015). Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci, 16, 579–594.Google Scholar
Patel, S., Hill, M. N., Cheer, J. F., et al. (2017). The endocannabinoid system as a target for novel anxiolytic drugs. Neurosci Biobehav Rev, 76, 56–66.Google Scholar
Patel, S., Roelke, C. T., Rademacher, D. J., et al. (2004). Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology, 145, 5431–5438.Google Scholar
Pava, M. J., Makriyannis, A., and Lovinger, D. M. (2016). Endocannabinoid signaling regulates sleep stability. PLoS ONE, 11, e0152473.Google Scholar
Pertwee, R. G., Howlett, A. C., Abood, M. E., et al. (2010). International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: Beyond CB1 and CB2. Pharmacol Rev, 62, 588–631.Google Scholar
Pertwee, R. G., and Ross, R. A. (2002). Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fat Acids, 66, 101–121.Google Scholar
Petrie, G. N., Nastase, A. S., Aukema, R. J., et al. (2021). Endocannabinoids, cannabinoids and the regulation of anxiety. Neuropharmacology, 195, 108626.Google Scholar
Petrosino, S., Schiano Moriello, A., Cerrato, S., et al. (2016). The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels. Br J Pharmacol, 173, 1154–1162.Google Scholar
Piette, C., Cui, Y., Gervasi, N., et al. (2020). Lights on endocannabinoid-mediated synaptic potentiation. Front Mol Neurosci, 13, 132.Google Scholar
Ren, M., Tang, Z., Wu, X., et al. (2019). The origins of cannabis smoking: Chemical residue evidence from the first millennium BCE in the Pamirs. Sci Adv, 5, 1–8.Google Scholar
Ryberg, E., Larsson, N., Sjögren, S., et al. (2007). The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol, 152, 1092–1101.CrossRefGoogle ScholarPubMed
Shao, Z., Yin, J., Chapman, K., et al. (2016). High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature, 540, 602–606.Google Scholar
Smith, P. B., and Martin, B. R. (1992). Spinal mechanisms of Δ9-tetrahydrocannabinol-induced analgesia. Brain Res, 578, 8–12.Google Scholar
Soria-Gomez, E., Pagano Zottola, A. C., Mariani, Y., et al. (2021). Subcellular specificity of cannabinoid effects in striatonigral circuits. Neuron, 109, 1513–1526.Google Scholar
Turner, S. E., Williams, C. M., Iversen, L., et al. (2017). Molecular pharmacology of phytocannabinoids. Prog Chem Org Nat Prod, 103, 61–101.Google Scholar
Valenti, M., Viganò, D., Casico, M. G., et al. (2004). Differential diurnal variations of anandamide and 2-arachidonoyl-glycerol levels in rat brain. Cell Mol Life Sci, 61, 945–950.Google Scholar
Vaughn, L. K., Denning, G., Stuhr, K. L., et al. (2010). Endocannabinoid signalling: Has it got rhythm? Br J Pharmacol, 160, 530–543.Google Scholar
Walker, J. M., and Huang, S. M. (2002). Cannabinoid analgesia. Pharmacol Ther, 95, 127–135.Google Scholar
Watkins, B. A., and Kim, J. (2015). The endocannabinoid system: Directing eating behavior and macronutrient metabolism. Front Psychol, 5, 1506.Google Scholar
Xing, C., Zhuang, Y., Xu, T. H., et al. (2020). Cryo-EM structure of the human cannabinoid receptor CB2-Gi signaling complex. Cell, 180, 645–654.Google Scholar
Zygmunt, P. M., Petersson, J., Andersson, D. A., et al. (1999). Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature, 400, 452–457.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×