Endocannabinoid System


The endocannabinoid system (ECS) is defined as the signalling system composed of: (1) the two G‐protein‐coupled receptors known as cannabinoid receptors of type‐1 and ‐2 (CB1 and CB2); (2) the two most studied endogenous agonists of such receptors, the endocannabinoids anandamide (N‐arachidonoyl‐ethanolamine) and 2‐AG (2‐arachidonoyl‐glycerol); (3) enzymes and other proteins regulating the tissue levels of endocannabinoids; and (4) enzymes and other proteins that, together with endocannabinoids, regulate the activity of cannabinoid receptors. A key role of the ECS is emerging in the control not only of central and peripheral nervous system functions, but also of most aspects of mammalian physiology, including energy intake, processing and storage, the immune response, reproduction and cell fate. The ECS is also subject to dysregulation, and this seems to contribute to the symptoms and progress of several diseases. Hence, the possibility of developing new therapies starting from our increasing knowledge of the ECS is discussed.

Key Concepts:

  • Endocannabinoids are local mediators with autocrine or paracrine function.

  • Endocannabinoids are usually produced de novo and ‘on demand’ following elevation of intracellular Ca2+ concentrations.

  • Endocannabinoids often act in the central nervous system as ‘retrograde neuromodulators’, that is, they are released from post‐synaptic neurons and act at cannabinoid CB1 receptors on pre‐synaptic axon terminals.

  • Endocannabinoids possess immune‐modulatory functions and usually inhibit cytokine release from immune cells and regulate the migration of the latter.

  • Endocannabinoids are key regulators of food intake, gastrointestinal function, energy storage in the adipose tissue and energy processing by the liver and the skeletal muscle.

  • Endocannabinoids are deeply involved in pain processing at peripheral, spinal and supra‐spinal sites.

  • Endocannabinoids regulate both male and female reproduction.

  • Endocannabinoid can differentially affect cell fate in healthy and cancer cells by regulating differentiation, proliferation and apoptosis.

  • Endocannabinoids, and anandamide in particular, also directly interact with non‐CB1, non‐CB2 receptors, the most studied of which is the transient receptor potential vanilloid type‐1 (TRPV1) channel.

  • Dysregulation of the ECS underlies several neurological, immune and metabolic disorders, and therapeutic strategies manipulating the ECS are being developed.

Keywords: cannabinoid; receptor; arachidonic acid; obesity; neuromodulator; pain; Pharmacology

Figure 1.

From THC to endocannabinoids. Chemical structures of Cannabis sativa main psychoactive constituent, (‐)‐Δ9‐tetrahydrocannabinol, and of the two most studied endocannabinoids, anandamide and 2‐arachidonoylglycerol.

Figure 2.

Retrograde signalling by endocannabinoids. Schematic representation of different types of endocannabinoid‐ and CB1‐mediated retrograde signalling in the brain. When their receptor is preferentially distributed presynaptically (as in the case of cannabinoid CB1 receptors), signals produced postsynaptically might act retrogradely to reduce excitatory and inhibitory neurotransmitter release in a way that is either ‘homosynaptic metabotropic‐driven’ (1) or ‘depolarisation‐driven’ (i.e. depolarisation‐induced suppression of excitatory or inhibitory signalling, [DSE or DSI]) (2). One such signal for at least the former type of synaptic signalling is 2‐arachidonoylglycerol (2‐AG), since its Ca2+‐sensitive biosynthetic machinery, comprising phospholipase Cβ (PLCβ) and diacylglycerol lipase‐α (DAGLα), is located on the somatodendritic membrane in proximity of metabotropic glutamate or acetylcholine receptors (e.g. mGluR1 or mGluR5 or M1 receptors), their G‐protein, Gq/11, and the scaffolding protein, Homer 1, as well as of inositol‐tris‐phosphate (IP3) receptors on the endoplasmic reticulum. In this way, activation of the metabotropic receptor can stimulate PLCβ via Gq/11, and produce diacylgycerol substrates for DAGLα, and, through activation of IP3 receptors, release from the ER the Ca2+ necessary for DAGL‐α activity. In retrograde signalling, the enzyme responsible for inactivation of the signal should be presynaptic, as is the case of the major 2‐AG degrading enzyme, monoacylglycerol lipase (MAGL). Lipophilic retrograde neuromodulators such as the endocannabinoids can also act at synapses near to, but different from, those from the activity of which the signal is ultimately generated, as in ‘heterosynaptic metabotropic‐driven’ retrograde signalling (3). Solid arrows denote activation, transformation or movement; broken arrows denote inhibition; small circles denote neurotransmitters; large circles denote secretory vesicles.

Figure 3.

Endocannabinoid system‐based therapeutic drugs. Chemical structures of the FAAH inhibitor, PF04457845, currently undergoing clinical trials, of the CB1 antagonist/inverse agonist, rimonabant, previously marketed as Acomplia, and of cannabidiol, which, together with THC, is the major active principle of Sativex.



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Di Marzo, Vincenzo(Jun 2011) Endocannabinoid System. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023403]