The Function of the Endocannabinoid System

doi:10.1017/9781108943246.003

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

Nathan D. Winters and

Sachin Patel

Edited by

Deepak Cyril D'Souza,

David Castle and

Sir Robin Murray

Show author details

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

Book contents

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

endocannabinoids cannabinoid receptors 2-arachidonoylglycerol anandamide

Information

Type: Chapter
Information: Marijuana and Madness , pp. 12 - 20
DOI: https://doi.org/10.1017/9781108943246.003 [Opens in a new window]
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.)

Book purchase

Temporarily unavailable

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.CrossRef Google Scholar PubMed

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.CrossRef Google Scholar PubMed

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). Gα_s 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.CrossRef Google Scholar PubMed

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.CrossRef Google Scholar PubMed

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.CrossRef Google Scholar PubMed

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

Accessibility standard: Unknown

Why this information is here

This section outlines the accessibility features of this content - including support for screen readers, full keyboard navigation and high-contrast display options. This may not be relevant for you.

Accessibility Information

Accessibility compliance for the HTML of this chapter is currently unknown and may be updated in the future.