Endocannabinoid system

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system (including the brain) and peripheral nervous system.^[1]^[2] The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility,^[3] pregnancy,^[4] pre- and postnatal development,^[5]^[6]^[7] various activity of immune system,^[8] appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis.^[9]^[10] The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.^[11]

Two primary cannabinoid receptors have been identified: CB1, first cloned (or isolated) in 1990; and CB2, cloned in 1993. CB1 receptors are found predominantly in the brain and nervous system, as well as in peripheral organs and tissues, and are the main molecular target of the endogenous partial agonist, anandamide, as well as exogenous tetrahydrocannabinol, the most known active component of cannabis. Endocannabinoid 2-arachidonoylglycerol (2-AG), which was found to be two and three orders of magnitude more abundant in mammalian brain than anandamide, acts as a full agonist at both CB receptors.^[12]

The endocannabinoid system is sometimes referred to as the endocannabinoidome or expanded endocannabinoid system.^[13]^[14]^[15]^[16]

^ Freitas HR, Ferreira GD, Trevenzoli IH, Oliveira KJ, de Melo Reis RA (November 2017). "Fatty Acids, Antioxidants and Physical Activity in Brain Aging". Nutrients. 9 (11): 1263. doi:10.3390/nu9111263. PMC 5707735. PMID 29156608.
^ Freitas HR, Isaac AR, Malcher-Lopes R, Diaz BL, Trevenzoli IH, De Melo Reis RA (December 2018). "Polyunsaturated fatty acids and endocannabinoids in health and disease". Nutritional Neuroscience. 21 (10): 695–714. doi:10.1080/1028415X.2017.1347373. PMID 28686542. S2CID 40659630.
^ Klein C, Hill MN, Chang SC, Hillard CJ, Gorzalka BB (June 2012). "Circulating endocannabinoid concentrations and sexual arousal in women". The Journal of Sexual Medicine. 9 (6): 1588–601. doi:10.1111/j.1743-6109.2012.02708.x. PMC 3856894. PMID 22462722.
^ Wang H, Xie H, Dey SK (June 2006). "Endocannabinoid signaling directs periimplantation events". The AAPS Journal. 8 (2): E425-32. doi:10.1007/BF02854916. PMC 3231559. PMID 16808046.
^ Freitas HR, Isaac AR, Silva TM, Diniz GO, Dos Santos Dabdab Y, Bockmann EC, et al. (September 2019). "Cannabinoids Induce Cell Death and Promote P2X7 Receptor Signaling in Retinal Glial Progenitors in Culture". Molecular Neurobiology. 56 (9): 6472–6486. doi:10.1007/s12035-019-1537-y. PMID 30838518. S2CID 71143662.
^ Freitas HR, Reis RA, Ventura AL, França GR (December 2019). "Interaction between cannabinoid and nucleotide systems as a new mechanism of signaling in retinal cell death". Neural Regeneration Research. 14 (12): 2093–2094. doi:10.4103/1673-5374.262585. PMC 6788250. PMID 31397346.
^ Fride E (October 2004). "The endocannabinoid-CB(1) receptor system in pre- and postnatal life". European Journal of Pharmacology. SPECIAL CELEBRATORY VOLUME 500 Dedicated to Professor David de Wied Honorary and Founding Editor. 500 (1–3): 289–97. doi:10.1016/j.ejphar.2004.07.033. PMID 15464041.
^ Pandey R, Mousawy K, Nagarkatti M, Nagarkatti P (August 2009). "Endocannabinoids and immune regulation". Pharmacological Research. 60 (2): 85–92. doi:10.1016/j.phrs.2009.03.019. PMC 3044336. PMID 19428268.
^ Aizpurua-Olaizola O, Elezgarai I, Rico-Barrio I, Zarandona I, Etxebarria N, Usobiaga A (January 2017). "Targeting the endocannabinoid system: future therapeutic strategies". Drug Discovery Today. 22 (1): 105–110. doi:10.1016/j.drudis.2016.08.005. PMID 27554802. S2CID 3460960.
^ Donvito G, Nass SR, Wilkerson JL, Curry ZA, Schurman LD, Kinsey SG, Lichtman AH (January 2018). "The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain". Neuropsychopharmacology. 43 (1): 52–79. doi:10.1038/npp.2017.204. PMC 5719110. PMID 28857069.
^ de Melo Reis RA, Isaac AR, Freitas HR, de Almeida MM, Schuck PF, Ferreira GC, et al. (2021). "Quality of Life and a Surveillant Endocannabinoid System". Frontiers in Neuroscience. 15: 747229. doi:10.3389/fnins.2021.747229. PMC 8581450. PMID 34776851.
^ Baggelaar MP, Maccarrone M, van der Stelt M (July 2018). "2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain". Progress in Lipid Research. 71: 1–17. doi:10.1016/j.plipres.2018.05.002. hdl:1887/67627. PMID 29751000.
^ Di Marzo, Vincenzo (30 September 2020). "The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders". Dialogues in Clinical Neuroscience. 22 (3): 259–269. doi:10.31887/DCNS.2020.22.3/vdimarzo. ISSN 1958-5969. PMC 7605024. PMID 33162769.
^ Di Marzo, Vincenzo (19 September 2014). The Endocannabinoidome: The World of Endocannabinoids and Related Mediators. Elsevier Science. ISBN 9780124201262.
^ Di Marzo, Vincenzo; Piscitelli, Fabiana (October 2015). "The Endocannabinoid System and its Modulation by Phytocannabinoids". Neurotherapeutics. 12 (4): 692–698. doi:10.1007/s13311-015-0374-6. ISSN 1933-7213. PMC 4604172. PMID 26271952.
^ Muller, Chanté; Morales, Paula; Reggio, Patricia H. (2019). "Cannabinoid Ligands Targeting TRP Channels". Frontiers in Molecular Neuroscience. 11: 487. doi:10.3389/fnmol.2018.00487. ISSN 1662-5099. PMC 6340993. PMID 30697147.

[1] Freitas HR, Ferreira GD, Trevenzoli IH, Oliveira KJ, de Melo Reis RA (November 2017). "Fatty Acids, Antioxidants and Physical Activity in Brain Aging". Nutrients. 9 (11): 1263. doi:10.3390/nu9111263. PMC 5707735. PMID 29156608.

[2] Freitas HR, Isaac AR, Malcher-Lopes R, Diaz BL, Trevenzoli IH, De Melo Reis RA (December 2018). "Polyunsaturated fatty acids and endocannabinoids in health and disease". Nutritional Neuroscience. 21 (10): 695–714. doi:10.1080/1028415X.2017.1347373. PMID 28686542. S2CID 40659630.

[3] Klein C, Hill MN, Chang SC, Hillard CJ, Gorzalka BB (June 2012). "Circulating endocannabinoid concentrations and sexual arousal in women". The Journal of Sexual Medicine. 9 (6): 1588–601. doi:10.1111/j.1743-6109.2012.02708.x. PMC 3856894. PMID 22462722.

[4] Wang H, Xie H, Dey SK (June 2006). "Endocannabinoid signaling directs periimplantation events". The AAPS Journal. 8 (2): E425-32. doi:10.1007/BF02854916. PMC 3231559. PMID 16808046.

[5] Freitas HR, Isaac AR, Silva TM, Diniz GO, Dos Santos Dabdab Y, Bockmann EC, et al. (September 2019). "Cannabinoids Induce Cell Death and Promote P2X7 Receptor Signaling in Retinal Glial Progenitors in Culture". Molecular Neurobiology. 56 (9): 6472–6486. doi:10.1007/s12035-019-1537-y. PMID 30838518. S2CID 71143662.

[6] Freitas HR, Reis RA, Ventura AL, França GR (December 2019). "Interaction between cannabinoid and nucleotide systems as a new mechanism of signaling in retinal cell death". Neural Regeneration Research. 14 (12): 2093–2094. doi:10.4103/1673-5374.262585. PMC 6788250. PMID 31397346.

[7] Fride E (October 2004). "The endocannabinoid-CB(1) receptor system in pre- and postnatal life". European Journal of Pharmacology. SPECIAL CELEBRATORY VOLUME 500 Dedicated to Professor David de Wied Honorary and Founding Editor. 500 (1–3): 289–97. doi:10.1016/j.ejphar.2004.07.033. PMID 15464041.

[8] Pandey R, Mousawy K, Nagarkatti M, Nagarkatti P (August 2009). "Endocannabinoids and immune regulation". Pharmacological Research. 60 (2): 85–92. doi:10.1016/j.phrs.2009.03.019. PMC 3044336. PMID 19428268.

[9] Aizpurua-Olaizola O, Elezgarai I, Rico-Barrio I, Zarandona I, Etxebarria N, Usobiaga A (January 2017). "Targeting the endocannabinoid system: future therapeutic strategies". Drug Discovery Today. 22 (1): 105–110. doi:10.1016/j.drudis.2016.08.005. PMID 27554802. S2CID 3460960.

[10] Donvito G, Nass SR, Wilkerson JL, Curry ZA, Schurman LD, Kinsey SG, Lichtman AH (January 2018). "The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain". Neuropsychopharmacology. 43 (1): 52–79. doi:10.1038/npp.2017.204. PMC 5719110. PMID 28857069.

[11] Melo Reis RA, Isaac AR, Freitas HR, de Almeida MM, Schuck PF, Ferreira GC, et al. (2021). "Quality of Life and a Surveillant Endocannabinoid System". Frontiers in Neuroscience. 15: 747229. doi:10.3389/fnins.2021.747229. PMC 8581450. PMID 34776851.

[12] Baggelaar MP, Maccarrone M, van der Stelt M (July 2018). "2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain". Progress in Lipid Research. 71: 1–17. doi:10.1016/j.plipres.2018.05.002. hdl:1887/67627. PMID 29751000.

[13] Di Marzo, Vincenzo (30 September 2020). "The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders". Dialogues in Clinical Neuroscience. 22 (3): 259–269. doi:10.31887/DCNS.2020.22.3/vdimarzo. ISSN 1958-5969. PMC 7605024. PMID 33162769.

[14] Di Marzo, Vincenzo (19 September 2014). The Endocannabinoidome: The World of Endocannabinoids and Related Mediators. Elsevier Science. ISBN 9780124201262.

[15] Di Marzo, Vincenzo; Piscitelli, Fabiana (October 2015). "The Endocannabinoid System and its Modulation by Phytocannabinoids". Neurotherapeutics. 12 (4): 692–698. doi:10.1007/s13311-015-0374-6. ISSN 1933-7213. PMC 4604172. PMID 26271952.

[16] Muller, Chanté; Morales, Paula; Reggio, Patricia H. (2019). "Cannabinoid Ligands Targeting TRP Channels". Frontiers in Molecular Neuroscience. 11: 487. doi:10.3389/fnmol.2018.00487. ISSN 1662-5099. PMC 6340993. PMID 30697147.

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