View source for Endocannabinoid system

{{Short description|Biological system of neurotransmitters}}
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[[File:2-arachidonoylglycerol 3D BS.png|thumb|3D model of [[2-Arachidonoylglycerol]], an endocannaboid]]
{{Use dmy dates|date=October 2017}}
The '''endocannabinoid system''' ('''ECS''') is a biological system composed of [[endocannabinoids]], which are [[Neurotransmitter|neurotransmitters]] that bind to [[cannabinoid receptors]], and cannabinoid receptor proteins that are expressed throughout the [[central nervous system]] (including the [[brain]]) and [[peripheral nervous system]].<ref>{{cite journal | vauthors = Freitas HR, Ferreira GD, Trevenzoli IH, Oliveira KJ, de Melo Reis RA | title = Fatty Acids, Antioxidants and Physical Activity in Brain Aging | journal = Nutrients | volume = 9 | issue = 11 | pages = 1263 | date = November 2017 | pmid = 29156608 | pmc = 5707735 | doi = 10.3390/nu9111263 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Freitas HR, Isaac AR, Malcher-Lopes R, Diaz BL, Trevenzoli IH, De Melo Reis RA | s2cid = 40659630 | title = Polyunsaturated fatty acids and endocannabinoids in health and disease | journal = Nutritional Neuroscience | volume = 21 | issue = 10 | pages = 695–714 | date = December 2018 | pmid = 28686542 | doi = 10.1080/1028415X.2017.1347373 }}</ref> The endocannabinoid system is still not fully understood, but may be involved in regulating physiological and [[cognitive process]]es, including [[fertility]],<ref>{{cite journal | vauthors = Klein C, Hill MN, Chang SC, Hillard CJ, Gorzalka BB | title = Circulating endocannabinoid concentrations and sexual arousal in women | journal = The Journal of Sexual Medicine | volume = 9 | issue = 6 | pages = 1588–601 | date = June 2012 | pmid = 22462722 | pmc = 3856894 | doi = 10.1111/j.1743-6109.2012.02708.x }}</ref> [[pregnancy]],<ref>{{cite journal | vauthors = Wang H, Xie H, Dey SK | title = Endocannabinoid signaling directs periimplantation events | journal = The AAPS Journal | volume = 8 | issue = 2 | pages = E425-32 | date = June 2006 | pmid = 16808046 | pmc = 3231559 | doi = 10.1007/BF02854916 }}</ref> [[Prenatal development|pre]]- and [[Postpartum period|postnatal]] development,<ref>{{cite journal | vauthors = Freitas HR, Isaac AR, Silva TM, Diniz GO, Dos Santos Dabdab Y, Bockmann EC, Guimarães MZ, da Costa Calaza K, de Mello FG, Ventura AL, de Melo Reis RA, França GR | s2cid = 71143662 | display-authors = 6 | title = Cannabinoids Induce Cell Death and Promote P2X7 Receptor Signaling in Retinal Glial Progenitors in Culture | journal = Molecular Neurobiology | volume = 56 | issue = 9 | pages = 6472–6486 | date = September 2019 | pmid = 30838518 | doi = 10.1007/s12035-019-1537-y }}</ref><ref>{{cite journal | vauthors = Freitas HR, Reis RA, Ventura AL, França GR | title = Interaction between cannabinoid and nucleotide systems as a new mechanism of signaling in retinal cell death | journal = Neural Regeneration Research | volume = 14 | issue = 12 | pages = 2093–2094 | date = December 2019 | pmid = 31397346 | pmc = 6788250 | doi = 10.4103/1673-5374.262585 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Fride E | title = The endocannabinoid-CB(1) receptor system in pre- and postnatal life | journal = European Journal of Pharmacology | volume = 500 | issue = 1–3 | pages = 289–97 | date = October 2004 | pmid = 15464041 | doi = 10.1016/j.ejphar.2004.07.033 | series = SPECIAL CELEBRATORY VOLUME 500 Dedicated to Professor David de Wied Honorary and Founding Editor }}</ref> various activity of immune system,<ref>{{cite journal | vauthors = Pandey R, Mousawy K, Nagarkatti M, Nagarkatti P | title = Endocannabinoids and immune regulation | journal = Pharmacological Research | volume = 60 | issue = 2 | pages = 85–92 | date = August 2009 | pmid = 19428268 | pmc = 3044336 | doi = 10.1016/j.phrs.2009.03.019 }}</ref> [[appetite]], [[nociception|pain-sensation]], [[Mood (psychology)|mood]], and [[memory]], and in mediating the [[pharmacological]] effects of [[cannabis (drug)|cannabis]].<ref>{{cite journal | vauthors = Aizpurua-Olaizola O, Elezgarai I, Rico-Barrio I, Zarandona I, Etxebarria N, Usobiaga A | title = Targeting the endocannabinoid system: future therapeutic strategies | journal = Drug Discovery Today | volume = 22 | issue = 1 | pages = 105–110 | date = January 2017 | pmid = 27554802 | doi = 10.1016/j.drudis.2016.08.005 | s2cid = 3460960 | url = https://figshare.com/articles/journal_contribution/5028362 }}</ref><ref>{{cite journal | vauthors = Donvito G, Nass SR, Wilkerson JL, Curry ZA, Schurman LD, Kinsey SG, Lichtman AH | title = The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain | journal = Neuropsychopharmacology | volume = 43 | issue = 1 | pages = 52–79 | date = January 2018 | pmid = 28857069 | pmc = 5719110 | doi = 10.1038/npp.2017.204 }}</ref> The ECS plays an important role in multiple aspects of [[Neuron|neural]] functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.<ref>{{cite journal | vauthors = de Melo Reis RA, Isaac AR, Freitas HR, de Almeida MM, Schuck PF, Ferreira GC, Andrade-da-Costa BL, Trevenzoli IH | display-authors = 6 | title = Quality of Life and a Surveillant Endocannabinoid System | journal = Frontiers in Neuroscience | volume = 15 | pages = 747229 | date = 2021 | pmid = 34776851 | pmc = 8581450 | doi = 10.3389/fnins.2021.747229 | doi-access = free }}</ref>

Two primary cannabinoid receptors have been identified: [[CB1 receptor|CB1]], first cloned (or isolated) in 1990; and [[CB2 receptor|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 fatty-acid neurotransmitter [[anandamide]], as well as the most known active component of cannabis, [[tetrahydrocannabinol]] (THC). Another endocannabinoid, [[2-arachidonoylglycerol]] (2-AG), also interacts with both CB receptors. It is significantly more abundant in the mammalian brain than anandamide, exceeding it by two to three orders of magnitude. <ref>{{cite journal | vauthors = Baggelaar MP, Maccarrone M, van der Stelt M | title = 2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain | journal = Progress in Lipid Research | volume = 71 | pages = 1–17 | date = July 2018 | pmid = 29751000 | doi = 10.1016/j.plipres.2018.05.002 | doi-access = free | hdl = 1887/67627 | hdl-access = free }}</ref>

The endocannabinoid system is sometimes called the endocannabinoidome or the expanded endocannabinoid system, as it includes a broader range of lipid mediators, receptors, and enzymes beyond CB1 and CB2.<ref>{{Cite journal |last=Di Marzo |first=Vincenzo |date=2020-09-30 |title=The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders |journal=Dialogues in Clinical Neuroscience |language=en |volume=22 |issue=3 |pages=259–269 |doi=10.31887/DCNS.2020.22.3/vdimarzo |pmid=33162769 |pmc=7605024 |issn=1958-5969}}</ref><ref>{{Cite book |last=Di Marzo |first=Vincenzo |title=The Endocannabinoidome: The World of Endocannabinoids and Related Mediators |date=19 September 2014 |publisher=Elsevier Science |url=https://www.sciencedirect.com/book/9780124201262/the-endocannabinoidome#book-description |isbn=9780124201262 }}</ref><ref>{{Cite journal |last1=Di Marzo |first1=Vincenzo |last2=Piscitelli |first2=Fabiana |date=October 2015 |title=The Endocannabinoid System and its Modulation by Phytocannabinoids |journal=Neurotherapeutics |language=en |volume=12 |issue=4 |pages=692–698 |doi=10.1007/s13311-015-0374-6 |pmid=26271952 |pmc=4604172 |issn=1933-7213}}</ref><ref>{{Cite journal |last1=Muller |first1=Chanté |last2=Morales |first2=Paula |last3=Reggio |first3=Patricia H. |date=2019 |title=Cannabinoid Ligands Targeting TRP Channels |journal=Frontiers in Molecular Neuroscience |volume=11 |page=487 |doi=10.3389/fnmol.2018.00487 |pmid=30697147 |pmc=6340993 |issn=1662-5099 |doi-access=free }}</ref>

== Basic overview ==
The endocannabinoid system, broadly speaking, includes:
* [[Endocannabinoids]], which are the physiological [[Ligand (biochemistry)|ligands]], or connecting substances, for the cannabinoid receptors. The main endocannabinoids are [[anandamide]] (''N''-arachidonoylethanolamide) and [[2-Arachidonoylglycerol|2-AG]] (2-arachidonoylglycerol), which are in the same class of chemical compounds, called [[N-Acylethanolamine|''N''-acylethanolamines]] (NAEs). Endocannabinoids are all [[eicosanoid]]s, another class of compound.<ref name="Pertwee2006">{{cite journal |vauthors=Pertwee RG |date=April 2006 |title=The pharmacology of cannabinoid receptors and their ligands: an overview |journal=International Journal of Obesity |volume=30 |issue=Suppl 1 |pages=S13–8 |doi=10.1038/sj.ijo.0803272 |pmid=16570099 |doi-access=free}}</ref>
* The enzymes that synthesize (create) and degrade (break down) the endocannabinoids, including [[fatty acid amide hydrolase]] and [[monoacylglycerol lipase]].
* The [[cannabinoid receptor]]s [[Cannabinoid receptor type 1|CB<sub>1</sub>]] and [[Cannabinoid receptor type 2|CB<sub>2</sub>]], two [[G protein-coupled receptors]] that are located in the central and peripheral nervous systems.
The [[neurons]], [[neural pathway]]s, and other cells where these molecules, enzymes, and one or both cannabinoid receptor types are all localized together collectively comprise the endocannabinoid system.

The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that [[cannabinoid]]s act as [[neuromodulator]]s,<ref>{{cite journal | vauthors = Fortin DA, Levine ES | title = Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons | journal = Cerebral Cortex| volume = 17 | issue = 1 | pages = 163–74 | year = 2007 | pmid = 16467564 | doi = 10.1093/cercor/bhj133 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Good CH | title = Endocannabinoid-dependent regulation of feedforward inhibition in cerebellar Purkinje cells | journal = Journal of Neuroscience| volume = 27 | issue = 1 | pages = 1–3 | year = 2007 | pmid = 17205618 | doi = 10.1523/JNEUROSCI.4842-06.2007 | pmc = 6672293 }}</ref><ref>{{cite journal | vauthors = Hashimotodani Y, Ohno-Shosaku T, Kano M | title = Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus | journal =  Journal of Neuroscience| volume = 27 | issue = 5 | pages = 1211–9 | year = 2007 | pmid = 17267577 | doi = 10.1523/JNEUROSCI.4159-06.2007 | pmc = 6673197 }}</ref> or regulators of many neurons and neural signals, for a variety of processes, including [[motor learning]],<ref name="Kishimoto Y, Kano M 2006 8829–37">{{cite journal | vauthors = Kishimoto Y, Kano M | title = Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning | journal =  Journal of Neuroscience| volume = 26 | issue = 34 | pages = 8829–37 | year = 2006 | pmid = 16928872 | doi = 10.1523/JNEUROSCI.1236-06.2006 | pmc = 6674369 }}</ref> [[appetite]],<ref name="DiMarzo" /> and [[pain]] sensation,<ref>{{cite journal | vauthors = Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH | title = Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase | journal = Proceedings of the National Academy of Sciences| volume = 98 | issue = 16 | pages = 9371–6 | date = July 2001 | pmid = 11470906 | pmc = 55427 | doi = 10.1073/pnas.161191698 | bibcode = 2001PNAS...98.9371C | display-authors = 1 | jstor = 3056353 | doi-access = free }}</ref> among other cognitive and physical processes. The CB1 receptor in the endocannabinoid system shows significant overlap with the [[orexinergic projection system]], a network of hypothalamic projections that regulate many of the same physical and cognitive functions.<ref name="Cannabinoid-Orexin systemic cross-talk" />  Moreover, CB1 is [[wikt:colocalize|colocalized]] on orexin projection neurons in the [[lateral hypothalamus]] and many output structures of the orexin system,<ref name="Cannabinoid-Orexin systemic cross-talk" /><ref name="CB1 Orexin Review">{{cite journal | vauthors = Watkins BA, Kim J | title = The endocannabinoid system: helps to direct eating behavior and macronutrient metabolism | journal = Frontiers in Psychology| volume = 5 | pages = 1506 | year = 2014 | pmid = 25610411 | pmc = 4285050 | doi = 10.3389/fpsyg.2014.01506 | quote = CB1 is present in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons in the gastrointestinal tract (Massa et al., 2005). Activation of CB1 is shown to modulate nutrient processing, such as gastric secretion, gastric emptying, and intestinal motility.&nbsp;... CB1 is shown to co-localize with the food intake inhibiting neuropeptide, corticotrophin-releasing hormone, in the paraventricular nucleus of the hypothalamus, and with the two orexigenic peptides, melanin-concentrating hormone in the lateral hypothalamus and with pre-pro-orexin in the ventromedial hypothalamus (Inui, 1999; Horvath, 2003). CB1 [[knockout mice]] showed higher levels of CRH mRNA, suggesting that hypothalamic EC receptors are involved in energy balance and may be able to mediate food intake (Cota et al., 2003).&nbsp;...  The ECS works through many anorexigenic and orexigenic pathways where ghrelin, leptin, adiponectin, endogenous opioids, and corticotropin-releasing hormones are involved (Viveros et al., 2008). | doi-access = free }}</ref> where the CB1 and [[orexin receptor 1]] (OX1) receptors physically and functionally join to form the CB1–OX1 [[GPCR oligomer|receptor heterodimer]].<ref name="Cannabinoid-Orexin systemic cross-talk">{{cite journal | vauthors = Flores A, Maldonado R, Berrendero F | title = Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far | journal = Frontiers in Neuroscience| volume = 7 | pages = 256 | year = 2013 | pmid = 24391536 | pmc = 3868890 | doi = 10.3389/fnins.2013.00256 | quote = Direct CB1-HcrtR1 interaction was first proposed in 2003 (Hilairet et al., 2003). Indeed, a 100-fold increase in the potency of hypocretin-1 to activate the ERK signaling was observed when CB1 and HcrtR1 were co-expressed&nbsp;...  In this study, a higher potency of hypocretin-1 to regulate CB1-HcrtR1 heteromer compared with the HcrtR1-HcrtR1 homomer was reported (Ward et al., 2011b). These data provide unambiguous identification of CB1-HcrtR1 heteromerization, which has a substantial functional impact.&nbsp;... The existence of a cross-talk between the hypocretinergic and endocannabinoid systems is strongly supported by their partially overlapping anatomical distribution and common role in several physiological and pathological processes. However, little is known about the mechanisms underlying this interaction.| doi-access = free }}<br />{{bull}}[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868890/figure/F1/ Figure 1: Schematic of brain CB1 expression and orexinergic neurons expressing OX1 or OX2]<br />{{bull}}[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868890/figure/F2/ Figure 2: Synaptic signaling mechanisms in cannabinoid and orexin systems]<br />{{bull}}[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868890/figure/F3/ Figure 3: Schematic of brain pathways involved in food intake]</ref><ref name="OX1-CB1 heterodimer review of function">{{cite journal | vauthors = Thompson MD, Xhaard H, Sakurai T, Rainero I, Kukkonen JP | title = OX1 and OX2 orexin/hypocretin receptor pharmacogenetics | journal = Frontiers in Neuroscience| volume = 8 | pages = 57 | year = 2014 | pmid = 24834023 | pmc = 4018553 | doi = 10.3389/fnins.2014.00057 | quote  = OX1–CB1 dimerization was suggested to strongly potentiate orexin receptor signaling, but a likely explanation for the signal potentiation is, instead, offered by the ability of OX1 receptor signaling to produce 2-arachidonoyl glycerol, a CB1 receptor ligand, and a subsequent co-signaling of the receptors (Haj-Dahmane and Shen, 2005; Turunen et al., 2012; Jäntti et al., 2013). However, this does not preclude dimerization.| doi-access = free }}</ref><ref name="Human heterodimers: OX1–OX2 OX1–CB1 OX2–CB1">{{cite journal | vauthors = Jäntti MH, Mandrika I, Kukkonen JP | title = Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors | journal = Biochemical and Biophysical Research Communications| volume = 445 | issue = 2 | pages = 486–90 | year = 2014 | pmid = 24530395 | doi = 10.1016/j.bbrc.2014.02.026 | quote = Orexin receptor subtypes readily formed homo- and hetero(di)mers, as suggested by significant BRET signals. CB1 receptors formed homodimers, and they also heterodimerized with both orexin receptors.&nbsp;... In conclusion, orexin receptors have a significant propensity to make homo- and heterodi-/oligomeric complexes. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations available for cannabinoid receptors.}}</ref>

=== Expression of receptors ===
{{further|topic=receptor localization|Cannabinoid receptor 1{{!}}Cannabinoid receptor type 1 (CB<sub>1</sub>)|Cannabinoid receptor type 2{{!}}Cannabinoid receptor type 2 (CB<sub>2</sub>)}}

Cannabinoid binding sites exist throughout the central and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB<sub>1</sub> and CB<sub>2</sub> receptors, which are expressed predominantly in the brain and immune system respectively.<ref name="Pertwee2008">{{cite journal |vauthors=Pertwee RG |title=The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin |journal= British Journal of Pharmacology|volume=153 |issue=2 |pages=199–215 |date=January 2008 |pmid=17828291 |pmc=2219532 |doi=10.1038/sj.bjp.0707442}}</ref> Density of expression varies based on species and correlates with the efficacy that cannabinoids will have in modulating specific aspects of behavior related to the site of expression. For example, in rodents, the highest concentration of cannabinoid binding sites are in the [[basal ganglia]] and [[cerebellum]], regions of the brain involved in the initiation and coordination of movement.<ref name="Elphick2001">{{cite journal |vauthors=Elphick MR, Egertová M |title=The neurobiology and evolution of cannabinoid signalling |journal= Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences|volume=356 |issue=1407 |pages=381–408 |date=March 2001 |pmid=11316486 |pmc=1088434 |doi=10.1098/rstb.2000.0787}}</ref> In humans, cannabinoid receptors exist in much lower concentration in these regions, which helps explain why cannabinoids possess a greater efficacy in altering rodent motor movements than they do in humans.

A recent analysis of cannabinoid binding in CB<sub>1</sub> and CB<sub>2</sub> receptor [[knockout mice]] found cannabinoid responsiveness even when these receptors were not being expressed, indicating that an additional binding receptor may be present in the brain.<ref name="Elphick2001" /> Binding has been demonstrated by [[2-arachidonoylglycerol]] (2-AG) on the [[TRPV1]] receptor suggesting that this receptor may be a candidate for the established response.<ref name="Puente2011">{{cite journal |vauthors=Puente N, Cui Y, Lassalle O, Lafourcade M, Georges F, Venance L, Grandes P, Manzoni OJ |s2cid=2879731 |title=Polymodal activation of the endocannabinoid system in the extended amygdala |journal= Nature Neuroscience|volume=14 |issue=12 |pages=1542–7 |date=December 2011 |pmid=22057189 |doi=10.1038/nn.2974}}</ref>

In addition to CB1 and CB2, certain [[orphan receptor]]s are known to bind endocannabinoids as well, including [[GPR18]], [[GPR55]] (a regulator of [[neuroimmune system|neuroimmune function]]), and [[GPR119]].  CB1 has also been noted to form a functional human [[GPCR oligomer|receptor heterodimer]] in orexin neurons with [[orexin receptor 1|OX1]], the CB1–OX1 receptor, which mediates feeding behavior and certain physical processes such as cannabinoid-induced [[pressor response]]s which are known to occur through signaling in the [[rostral ventrolateral medulla]].<ref name="CB1 RVLM">{{cite journal |vauthors=Ibrahim BM, Abdel-Rahman AA |title=Cannabinoid receptor 1 signaling in cardiovascular regulating nuclei in the brainstem: A review |journal= Journal of Advanced Research|volume=5 |issue=2 |pages=137–45 |year=2014 |pmid=25685481 |pmc=4294710 |doi=10.1016/j.jare.2013.03.008}}</ref><ref name="CB1, OX1, orexin-A – RVLM colocalization">{{cite journal |vauthors=Ibrahim BM, Abdel-Rahman AA |title=A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats |journal= Brain Research|volume=1622 |pages=51–63 |year=2015 |pmid=26096126 |pmc=4562882 |doi=10.1016/j.brainres.2015.06.011 |quote=Orexin receptor 1 (OX1R) signaling is implicated in cannabinoid receptor 1 (CB1R) modulation of feeding. Further, our studies established the dependence of the central CB1R-mediated pressor response on neuronal nitric oxide synthase (nNOS) and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation in the RVLM. We tested the novel hypothesis that brainstem orexin-A/OX1R signaling plays a pivotal role in the central CB1R-mediated pressor response. Our multiple labeling immunofluorescence findings revealed co-localization of CB1R, OX1R and the peptide orexin-A within the C1 area of the rostral ventrolateral medulla (RVLM). Activation of central CB1R&nbsp;... in conscious rats caused significant increases in BP and orexin-A level in RVLM neuronal tissue. Additional studies established a causal role for orexin-A in the central CB1R-mediated pressor response}}</ref>

=== Endocannabinoid synthesis, release, and degradation ===

During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the [[synaptic cleft]] which bind to cognate receptors expressed on the post-synaptic neuron.  Based upon the interaction between the transmitter and receptor, neurotransmitters may trigger a variety of effects in the post-synaptic cell, such as excitation, inhibition, or the initiation of [[second messenger system|second messenger]] cascades. Based on the cell, these effects may result in the on-site synthesis of endogenous cannabinoids [[anandamide]] or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium.<ref name="Pertwee2008" /> Expression appears to be exclusive, so that both types of endocannabinoids are not co-synthesized. This exclusion is based on synthesis-specific channel activation: a recent study found that in the bed nucleus of the [[stria terminalis]], calcium entry through voltage-sensitive calcium channels produced an L-type current resulting in 2-AG production, while activation of [[metabotropic glutamate receptor 1|mGluR1/5]] receptors triggered the synthesis of anandamide.<ref name="Puente2011" />

Evidence suggests that the depolarization-induced influx of calcium into the post-synaptic neuron causes the activation of an enzyme called [[transacylase]]. This enzyme is suggested to catalyze the first step of endocannabinoid biosynthesis by converting [[phosphatidylethanolamine]], a membrane-resident phospholipid, into [[N-acyl-phosphatidylethanolamine|''N''-acyl-phosphatidylethanolamine]] (NAPE). Experiments have shown that [[phospholipase D]] cleaves NAPE to yield anandamide.<ref>{{cite journal | vauthors = Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N | title = Molecular characterization of a phospholipase D generating anandamide and its congeners | journal = Journal of Biological Chemistry| volume = 279 | issue = 7 | pages = 5298–305 | date = February 2004 | pmid = 14634025 | doi = 10.1074/jbc.M306642200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Liu J, Wang L, Harvey-White J, Osei-Hyiaman D, Razdan R, Gong Q, Chan AC, Zhou Z, Huang BX, Kim HY, Kunos G | title = A biosynthetic pathway for anandamide | journal = Proceedings of the National Academy of Sciences| volume = 103 | issue = 36 | pages = 13345–50 | date = September 2006 | pmid = 16938887 | pmc = 1557387 | doi = 10.1073/pnas.0601832103 | bibcode = 2006PNAS..10313345L | doi-access = free }}</ref> This process is mediated by [[bile acids]].<ref name="Garau">{{cite journal | vauthors =  Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, Garau G | title = Structure of Human N-Acylphosphatidylethanolamine-Hydrolyzing Phospholipase D: Regulation of Fatty Acid Ethanolamide Biosynthesis by Bile Acids | journal = Structure | volume = 23 | issue = 3 | date = 2014 | pmid = 25684574 | doi = 10.1016/j.str.2014.12.018 | pages=598–604 | pmc=4351732}}</ref><ref name="Garau Gianpiero">{{cite journal | vauthors =  Margheritis E, Castellani B, Magotti P, Peruzzi S, Romeo E, Natali F, Mostarda S, Gioiello A, Piomelli D, Garau G | title = Bile Acid Recognition by NAPE-PLD | journal = ACS Chemical Biology | volume = 11 | issue = 10 | date = 2016 | pmid = 27571266 | doi = 10.1021/acschembio.6b00624 | pages=2908–2914 | pmc=5074845}}</ref>
In NAPE-phospholipase D ([[NAPEPLD]])-knockout mice, cleavage of NAPE is reduced in low calcium concentrations, but not abolished, suggesting multiple, distinct pathways are involved in anandamide synthesis.<ref>{{cite journal | vauthors = Leung D, Saghatelian A, Simon GM, Cravatt BF | title = Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids | journal = Biochemistry | volume = 45 | issue = 15 | pages = 4720–6 | date = April 2006 | pmid = 16605240 | pmc = 1538545 | doi = 10.1021/bi060163l }}</ref> The synthesis of 2-AG is less established and warrants further research.

Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to [[glial cell]] inactivation.  Endocannabinoids are taken up by a transporter on the glial cell and degraded by [[fatty acid amide hydrolase]] (FAAH), which cleaves anandamide into [[arachidonic acid]] and [[ethanolamine]] or [[monoacylglycerol lipase]] (MAGL), and 2-AG into arachidonic acid and glycerol.<ref>{{cite journal | vauthors = Pazos MR, Núñez E, Benito C, Tolón RM, Romero J | s2cid = 12588731 | title = Functional neuroanatomy of the endocannabinoid system | journal = Pharmacology Biochemistry and Behavior| volume = 81 | issue = 2 | pages = 239–47 | date = June 2005 | pmid = 15936805 | doi = 10.1016/j.pbb.2005.01.030 }}</ref> While arachidonic acid is a substrate for [[leukotriene]] and [[prostaglandin]] synthesis, it is unclear whether this degradative byproduct has unique functions in the [[central nervous system]].<ref>{{cite journal | vauthors = Yamaguchi T, Shoyama Y, Watanabe S, Yamamoto T | s2cid = 34809694 | title = Behavioral suppression induced by cannabinoids is due to activation of the arachidonic acid cascade in rats | journal = Brain Research| volume = 889 | issue = 1–2 | pages = 149–54 | date = January 2001 | pmid = 11166698 | doi = 10.1016/S0006-8993(00)03127-9 }}</ref><ref>{{cite journal | vauthors = Brock TG | title = Regulating leukotriene synthesis: the role of nuclear 5-lipoxygenase | journal =  Journal of Cellular Biochemistry| volume = 96 | issue = 6 | pages = 1203–11 | date = December 2005 | pmid = 16215982 | doi = 10.1002/jcb.20662 | hdl = 2027.42/49282 | s2cid = 18009424 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/49282/1/20662_ftp.pdf | doi-access = free }}</ref> Emerging data in the field also points to FAAH being expressed in postsynaptic neurons complementary to presynaptic neurons expressing cannabinoid receptors, supporting the conclusion that it is major contributor to the clearance and inactivation of anandamide and 2-AG after endocannabinoid reuptake.<ref name="Elphick2001" /> A neuropharmacological study demonstrated that an inhibitor of FAAH (URB597) selectively increases anandamide levels in the brain of rodents and primates. Such approaches could lead to the development of new drugs with analgesic, anxiolytic-like and antidepressant-like effects, which are not accompanied by overt signs of abuse liability.<ref>{{cite journal | vauthors = Clapper JR, Mangieri RA, Piomelli D | title = The endocannabinoid system as a target for the treatment of cannabis dependence | journal = Neuropharmacology | volume = 56 | issue = Suppl 1 | pages = 235–43 | year = 2009 | pmid = 18691603 | pmc = 2647947 | doi = 10.1016/j.neuropharm.2008.07.018 }}</ref>

=== Binding and intracellular effects ===

Cannabinoid receptors are G-protein coupled receptors located on the pre-synaptic membrane. While there have been some papers that have linked concurrent stimulation of [[dopamine]] and CB<sub>1</sub> receptors to an acute rise in [[cyclic adenosine monophosphate]] (cAMP) production, it is generally accepted that CB<sub>1</sub> activation via cannabinoids causes a decrease in cAMP concentration<ref>{{cite journal | vauthors = Kubrusly RC, Günter A, Sampaio L, Martins RS, Schitine CS, Trindade P, Fernandes A, Borelli-Torres R, Miya-Coreixas VS, Rego Costa AC, Freitas HR, Gardino PF, de Mello FG, Calaza KC, Reis RA | s2cid = 37166339 | display-authors = 6 | title = Neuro-glial cannabinoid receptors modulate signaling in the embryonic avian retina | journal = Neurochemistry International | volume = 112 | pages = 27–37 | date = January 2018 | pmid = 29108864 | doi = 10.1016/j.neuint.2017.10.016 | doi-access = free }}</ref> by inhibition of [[adenylyl cyclase]] and a rise in the concentration of [[mitogen-activated protein kinase]] (MAP kinase).<ref name="Pertwee2006" /><ref name="Elphick2001" /> The relative potency of different cannabinoids in inhibition of adenylyl cyclase correlates with their varying efficacy in behavioral assays. This inhibition of cAMP is followed by phosphorylation and subsequent activation of not only a suite of MAP kinases ([[P38 mitogen-activated protein kinases|p38]]/[[MAPK1|p42]]/[[ERK1|p44]]), but also the [[Phosphoinositide 3-kinase|PI3]]/[[Protein Kinase B|PKB]] and [[MAPK/ERK pathway|MEK/ERK pathway]].<ref name="Galve-Roperh_2002">{{cite journal | vauthors = Galve-Roperh I, Rueda D, Gómez del Pulgar T, Velasco G, Guzmán M | title = Mechanism of extracellular signal-regulated kinase activation by the CB(1) cannabinoid receptor | journal = Molecular Pharmacology | volume = 62 | issue = 6 | pages = 1385–92 | date = December 2002 | pmid = 12435806 | doi = 10.1124/mol.62.6.1385 | s2cid = 35655934 | url = http://pdfs.semanticscholar.org/86fb/0c19f6840aabd8451e02da25d4b20dbd0020.pdf | archive-url = https://web.archive.org/web/20190228053936/http://pdfs.semanticscholar.org/86fb/0c19f6840aabd8451e02da25d4b20dbd0020.pdf | url-status = dead | archive-date = 2019-02-28 }}</ref><ref name="Graham_2006">{{cite journal | vauthors = Graham ES, Ball N, Scotter EL, Narayan P, Dragunow M, Glass M | title = Induction of Krox-24 by endogenous cannabinoid type 1 receptors in Neuro2A cells is mediated by the MEK-ERK MAPK pathway and is suppressed by the phosphatidylinositol 3-kinase pathway | journal = The Journal of Biological Chemistry | volume = 281 | issue = 39 | pages = 29085–95 | date = September 2006 | pmid = 16864584 | doi = 10.1074/jbc.M602516200 | doi-access = free }}</ref> Results from rat hippocampal [[gene chip]] data after acute administration of [[tetrahydrocannabinol]] (THC) showed an increase in the expression of transcripts encoding [[myelin basic protein]], endoplasmic proteins, [[cytochrome oxidase]], and two cell adhesion molecules: [[NCAM]], and SC1; decreases in expression were seen in both [[calmodulin]] and [[ribosomal RNA]]s.<ref name="Kittler_2000">{{cite journal | vauthors = Kittler JT, Grigorenko EV, Clayton C, Zhuang SY, Bundey SC, Trower MM, Wallace D, Hampson R, Deadwyler S | title = Large-scale analysis of gene expression changes during acute and chronic exposure to [Delta]9-THC in rats | journal = Physiological Genomics | volume = 3 | issue = 3 | pages = 175–85 | date = September 2000 | pmid = 11015613 | doi = 10.1152/physiolgenomics.2000.3.3.175 | s2cid = 25959929 | url = http://pdfs.semanticscholar.org/c124/f719526827422c5876bb955090a63b839017.pdf | archive-url = https://web.archive.org/web/20190304045700/http://pdfs.semanticscholar.org/c124/f719526827422c5876bb955090a63b839017.pdf | url-status = dead | archive-date = 2019-03-04 }}</ref> In addition, CB1 activation has been demonstrated to increase the activity of transcription factors like [[c-Fos]] and [[Krox-24]].<ref name="Graham_2006" />

=== Binding and neuronal excitability ===
{{context|section|date=January 2014}}
The molecular mechanisms of the endocannabinoid system are primarily concerned with certain [[Voltage-gated ion channel|voltage-gated]] and [[Ligand-gated ion channel|ligand-gated]] channels, which can be directly affected by cannabinoids. More specifically, cannabinoids reduce calcium influx by blocking the activity of certain calcium channels, called voltage-dependent [[N-type calcium channel|N-]], [[P-type calcium channel|P]]/[[Q-type calcium channel|Q-]] and [[L-type calcium channel|L-type]] [[calcium channel]]s.<ref name=":1">{{cite journal | vauthors = Twitchell W, Brown S, Mackie K | title = Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons | journal = Journal of Neurophysiology| volume = 78 | issue = 1 | pages = 43–50 | year = 1997 | pmid = 9242259 | doi =  10.1152/jn.1997.78.1.43}}</ref><ref name="Guo">{{cite journal | vauthors = Guo J, Ikeda SR | title = Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons | journal = Molecular Pharmacology| volume = 65 | issue = 3 | pages = 665–74 | year = 2004 | pmid = 14978245 | doi = 10.1124/mol.65.3.665 | s2cid = 25065163 }}</ref> This reduction in activity means that depolarization of affected cells is less likely to occur, and thus neural signalling is reduced.<ref name=":1" /><ref name="Guo" /> In addition to acting on calcium channels, activation of [[Gi subunit|Gi/o]] and [[Gs subunit|Gs]], the two most commonly coupled G-proteins to cannabinoid receptors, has been shown to modulate [[potassium channel]] activity.  Recent studies have found that CB<sub>1</sub> activation specifically facilitates potassium ion flux through [[G protein-coupled inwardly-rectifying potassium channel|GIRKs]], a family of [[potassium channel]]s.<ref name="Guo" />  Immunohistochemistry experiments demonstrated that CB<sub>1</sub> is co-localized with GIRK and [[KCNA4|Kv1.4]] potassium channels, suggesting that these two may interact in physiological contexts.<ref>{{cite journal | vauthors = Binzen U, Greffrath W, Hennessy S, Bausen M, Saaler-Reinhardt S, Treede RD | s2cid = 11077423 | title = Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB<sub>1</sub> in rat dorsal root ganglion neurons | journal = Neuroscience | volume = 142 | issue = 2 | pages = 527–39 | year = 2006 | pmid = 16889902 | doi = 10.1016/j.neuroscience.2006.06.020 }}</ref>

In the [[central nervous system]], CB<sub>1</sub> receptors influence neuronal excitability, reducing the incoming synaptic input.<ref>{{cite journal | vauthors = Freund TF, Katona I, Piomelli D | title = Role of endogenous cannabinoids in synaptic signaling | journal = Physiological Reviews| volume = 83 | issue = 3 | pages = 1017–66 | year = 2003 | pmid = 12843414 | doi = 10.1152/physrev.00004.2003 | url = http://www.escholarship.org/uc/item/1633t2mf }}</ref>
This mechanism, known as [[presynaptic inhibition]], occurs when a postsynaptic neuron releases endocannabinoids in retrograde transmission, which then bind to cannabinoid receptors on the presynaptic terminal. CB<sub>1</sub> receptors then reduce the amount of neurotransmitter released, so that subsequent excitation in the presynaptic neuron results in diminished effects on the postsynaptic neuron. It is likely that presynaptic inhibition uses many of the same ion channel mechanisms listed above, although recent evidence has shown that CB<sub>1</sub> receptors can also regulate neurotransmitter release by a non-ion channel mechanism, i.e., through Gi/o-mediated inhibition of [[adenylyl cyclase]] and [[protein kinase A]].<ref>{{cite journal | vauthors = Chevaleyre V, Heifets BD, Kaeser PS, Südhof TC, Purpura DP, Castillo PE | title =  Endocannabinoid-Mediated Long-Term Plasticity Requires cAMP/PKA Signaling and RIM1α| journal = Neuron | volume = 54 | issue = 5 | pages = 801–12 | year = 2007 | pmid = 17553427 | pmc = 2001295 | doi = 10.1016/j.neuron.2007.05.020 }}</ref>
Direct effects of CB<sub>1</sub> receptors on membrane excitability have been reported, and strongly impact the firing of cortical neurons.<ref>{{cite journal | vauthors = Bacci A, Huguenard JR, Prince DA | s2cid = 4373585 | title = Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids | journal = Nature | volume = 431 | issue = 7006 | pages = 312–6 | year = 2004 | pmid = 15372034 | doi = 10.1038/nature02913 | bibcode = 2004Natur.431..312B }}</ref>
A series of behavioral experiments demonstrated that [[NMDAR]], an ionotropic [[glutamate receptor]], and the [[metabotropic glutamate receptor]]s (mGluRs) work in concert with CB<sub>1</sub> to induce [[analgesia]] in mice, although the mechanism underlying this effect is unclear.{{Citation needed|date=October 2015}}

==Potential functions==

=== Memory ===

Mice treated with THC show suppression of [[long-term potentiation]] in the hippocampus, a process that is essential for the formation and storage of long-term memory.<ref>{{cite journal | vauthors = Hampson RE, Deadwyler SA | title = Cannabinoids, hippocampal function and memory | journal = Life Sciences| volume = 65 | issue = 6–7 | pages = 715–23 | year = 1999 | pmid = 10462072 | doi = 10.1016/S0024-3205(99)00294-5 }}</ref>  These results may concur with anecdotal evidence suggesting that smoking cannabis impairs short-term memory.<ref name=Pertwee2001>{{cite journal | vauthors = Pertwee RG | s2cid = 25328510 | title = Cannabinoid receptors and pain | journal = Progress in Neurobiology| volume = 63 | issue = 5 | pages = 569–611 | year = 2001 | pmid = 11164622 | doi = 10.1016/S0301-0082(00)00031-9 }}</ref>  Consistent with this finding, mice without the CB<sub>1</sub> receptor show enhanced memory and long-term potentiation indicating that the endocannabinoid system may play a pivotal role in the extinction of old memories. One study found that the high-dose treatment of rats with the synthetic cannabinoid [[HU-210]] over several weeks resulted in stimulation of neural growth in the rats' [[Hippocampus#Role in general memory|hippocampus]] region, a part of the [[limbic system]] playing a part in the formation of [[declarative memory|declarative]] and [[Hippocampus#Role in spatial memory and navigation|spatial memories]], but did not investigate the effects on short-term or long-term memory.<ref name=Jiang2005>{{cite journal | vauthors = Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X | title = Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects | journal = Journal of Clinical Investigation| volume = 115 | issue = 11 | pages = 3104–16 | year = 2005 | pmid = 16224541 | pmc = 1253627 | doi = 10.1172/JCI25509 }}</ref> Taken together, these findings suggest that the effects of endocannabinoids on the various brain networks involved in learning and memory may vary.

==== Role in hippocampal neurogenesis ====

In the adult brain, the endocannabinoid system facilitates the [[neurogenesis]] of hippocampal [[granule cells]].<ref name=Jiang2005 /><ref name=Aguado2005>{{cite journal | vauthors = Aguado T, Monory K, Palazuelos J, Stella N, Cravatt B, Lutz B, Marsicano G, Kokaia Z, Guzmán M, Galve-Roperh I | title = The endocannabinoid system drives neural progenitor proliferation | journal =  The FASEB Journal| volume = 19 | issue = 12 | pages = 1704–6 | year = 2005 | pmid = 16037095 | doi = 10.1096/fj.05-3995fje | doi-access = free | s2cid = 42230 }}</ref> In the [[subgranular zone]] of the [[dentate gyrus]], multipotent neural progenitors (NP) give rise to [[daughter cell]]s that, over the course of several weeks, mature into granule cells whose axons project to and synapse onto  dendrites on the [[Cornu Ammonis region 3|CA3]] region.<ref>{{cite journal | vauthors = Christie BR, Cameron HA | title = Neurogenesis in the adult hippocampus | journal = Hippocampus | volume = 16 | issue = 3 | pages = 199–207 | year = 2006 | pmid = 16411231 | doi = 10.1002/hipo.20151 | s2cid = 30561899 }}</ref>  NPs in the hippocampus have been shown to possess fatty acid amide hydrolase (FAAH) and express CB<sub>1</sub> and utilize 2-AG.<ref name=Aguado2005 />  Intriguingly, CB<sub>1</sub> activation by endogenous or exogenous cannabinoids promote NP proliferation and differentiation; this activation is absent in CB<sub>1</sub> knockouts and abolished in the presence of antagonist.<ref name=Jiang2005 /><ref name=Aguado2005 />

==== Induction of synaptic depression ====
Endocannabinoids are known to influence [[synaptic plasticity]], and are in particular thought to mediate [[long-term depression]] (LTD, which refers to neuronal firing, not psychological depression). [[Neural facilitation#Short-term depression (STD)|Short-term depression]] (STD) has also been described (see the next paragraph). First reported in the [[striatum]],<ref>{{cite journal | vauthors = Gerdeman GL, Ronesi J, Lovinger DM | s2cid = 19803274 | title = Postsynaptic endocannabinoid release is critical to long-term depression in the striatum | journal = Nature Neuroscience | volume = 5 | issue = 5 | pages = 446–51 | date = May 2002 | pmid = 11976704 | doi = 10.1038/nn832 }}</ref> this system is known to function in several other brain structures such as the nucleus accumbens, amygdala, hippocampus, cerebral cortex, cerebellum, ventral tegmental area (VTA), brain stem, and superior colliculus.<ref name=":0">{{cite journal | vauthors = Heifets BD, Castillo PE | title = Endocannabinoid signaling and long-term synaptic plasticity | journal = Annual Review of Physiology | volume = 71 | issue = 1 | pages = 283–306 | date = 2009-02-12 | pmid = 19575681 | pmc = 4454279 | doi = 10.1146/annurev.physiol.010908.163149 }}</ref> Typically, these retrograde transmitters are released by the postsynaptic neuron and induce synaptic depression by activating the presynaptic CB1 receptors.<ref name=":0" />

It has further been suggested that different endocannabinoids, i.e., 2-AG and anandamide, might mediate different forms of synaptic depression through different mechanisms.<ref name="Puente2011" /> The study conducted with the [[Stria terminalis#Bed nucleus of the stria terminalis|bed nucleus of the stria terminalis]] found that the endurance of the depressant effects was mediated by two different signaling pathways based on the type of receptor activated. 2-AG was found to act on presynaptic CB<sub>1</sub> receptors to mediate retrograde STD following activation of L-type calcium channels, while anandamide was synthesized after [[Metabotropic glutamate receptor 5|mGluR5]] activation and triggered [[autocrine signalling]] onto postsynapic [[TRPV1]] receptors that induced LTD.<ref name="Puente2011" /> These findings provide the brain a direct mechanism to selectively inhibit neuronal excitability over variable time scales. By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs.

=== Appetite ===

Evidence for the role of the endocannabinoid system in food-seeking behavior comes from a variety of cannabinoid studies. Emerging data suggests that THC acts via CB<sub>1</sub> receptors in the hypothalamic nuclei to directly increase appetite.<ref name="Kirkham TC, Tucci SA 2006 272–92">{{cite journal | vauthors = Kirkham TC, Tucci SA | title = Endocannabinoids in appetite control and the treatment of obesity | journal = CNS Neurol Disord Drug Targets | volume = 5 | issue = 3 | pages = 272–92 | date = 2006 | pmid = 16787229 | doi = 10.2174/187152706777452272 }}</ref> It is thought that hypothalamic neurons tonically produce endocannabinoids that work to tightly regulate [[hunger]]. The amount of endocannabinoids produced is inversely correlated with the amount of [[leptin]] in the blood.<ref>{{cite journal | vauthors = Di Marzo V, Sepe N, De Petrocellis L, Berger A, Crozier G, Fride E, Mechoulam R | s2cid = 4425760 | title = Trick or treat from food endocannabinoids? | journal = Nature | volume = 396 | issue = 6712 | pages = 636–7 | date = December 1998 | pmid = 9872309 | doi = 10.1038/25267 | bibcode = 1998Natur.396..636D | url = https://escholarship.org/uc/item/1qh5k290 | doi-access = free }}</ref>  For example, mice without leptin not only become massively obese but express abnormally high levels of hypothalamic endocannabinoids as a compensatory mechanism.<ref name=DiMarzo>{{cite journal | vauthors = Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G | s2cid = 4350552 | title = Leptin-regulated endocannabinoids are involved in maintaining food intake | journal = Nature | volume = 410 | issue = 6830 | pages = 822–5 | date = April 2001 | pmid = 11298451 | doi = 10.1038/35071088 | bibcode = 2001Natur.410..822D }}</ref>  Similarly, when these mice were treated with an endocannabinoid inverse agonists, such as [[rimonabant]], food intake was reduced.<ref name="DiMarzo" />  When the CB<sub>1</sub> receptor is [[Knockout mouse|knocked out]] in mice, these animals tend to be leaner and less hungry than wild-type mice. A related study examined the effect of THC on the hedonic (pleasure) value of food and found enhanced dopamine release in the [[nucleus accumbens]] and increased pleasure-related behavior after administration of a sucrose solution.<ref>{{cite journal | vauthors = De Luca MA, Solinas M, Bimpisidis Z, Goldberg SR, Di Chiara G | title = Cannabinoid facilitation of behavioral and biochemical hedonic taste responses | journal = Neuropharmacology | volume = 63 | issue = 1 | pages = 161–8 | date = July 2012 | pmid = 22063718 | pmc = 3705914 | doi = 10.1016/j.neuropharm.2011.10.018 }}</ref>  A related study found that endocannabinoids affect taste perception in taste cells.<ref>{{cite journal | vauthors = Yoshida R, Ohkuri T, Jyotaki M, Yasuo T, Horio N, Yasumatsu K, Sanematsu K, Shigemura N, Yamamoto T, Margolskee RF, Ninomiya Y | title = Endocannabinoids selectively enhance sweet taste | journal =Proceedings of the National Academy of Sciences| volume = 107 | issue = 2 | pages = 935–9 | date = January 2010 | pmid = 20080779 | pmc = 2818929 | doi = 10.1073/pnas.0912048107 | bibcode = 2010PNAS..107..935Y | display-authors = 1 | jstor = 40535875 | doi-access = free }}</ref>  In taste cells, endocannabinoids were shown to selectively enhance the strength of neural signaling for sweet tastes, whereas leptin decreased the strength of this same response. While there is need for more research, these results suggest that cannabinoid activity in the hypothalamus and nucleus accumbens is related to appetitive, food-seeking behavior.<ref name="Kirkham TC, Tucci SA 2006 272–92" />

=== Energy balance and metabolism ===
The endocannabinoid system has been shown to have a [[homeostatic]] role by controlling several metabolic functions, such as energy storage and nutrient transport. It acts on peripheral tissues such as [[adipocytes]], [[hepatocytes]], the [[gastrointestinal tract]], the [[skeletal muscles]] and the endocrine [[pancreas]]. It has also been implied in modulating [[insulin sensitivity]]. Through all of this, the endocannabinoid system may play a role in clinical conditions, such as [[obesity]], [[diabetes]], and [[atherosclerosis]], which may also give it a [[cardiovascular]] role.<ref>{{cite journal | vauthors = Bellocchio L, Cervino C, Pasquali R, Pagotto U | title = The endocannabinoid system and energy metabolism | journal = Journal of Neuroendocrinology| volume = 20 | issue = 6 | pages = 850–7 | date = June 2008 | pmid = 18601709 | doi = 10.1111/j.1365-2826.2008.01728.x | s2cid = 6338960 | doi-access = free }}</ref>

=== Stress response ===
While the secretion of [[glucocorticoids]] in response to stressful stimuli is an adaptive response necessary for an organism to respond appropriately to a stressor, persistent secretion may be harmful. The endocannabinoid system has been implicated in the habituation of the [[hypothalamic-pituitary-adrenal axis]] (HPA axis) to repeated exposure to restraint stress. Studies have demonstrated differential synthesis of anandamide and 2-AG during tonic stress. A decrease of anandamide was found along the axis that contributed to basal hypersecretion of [[corticosterone]]; in contrast, an increase of 2-AG was found in the amygdala after repeated stress, which was negatively correlated to magnitude of the corticosterone response. All effects were abolished by the CB<sub>1</sub> antagonist [[AM251]], supporting the conclusion that these effects were cannabinoid-receptor dependent.<ref>{{cite journal | vauthors = Hill MN, McLaughlin RJ, Bingham B, Shrestha L, Lee TT, Gray JM, Hillard CJ, Gorzalka BB, Viau V | title = Endogenous cannabinoid signaling is essential for stress adaptation | journal = Proceedings of the National Academy of Sciences| volume = 107 | issue = 20 | pages = 9406–11 | date = May 2010 | pmid = 20439721 | pmc = 2889099 | doi = 10.1073/pnas.0914661107 | bibcode = 2010PNAS..107.9406H | doi-access = free }}</ref>  These findings show that anandamide and 2-AG divergently regulate the HPA axis response to stress: while habituation of the stress-induced HPA axis via 2-AG prevents excessive secretion of glucocorticoids to non-threatening stimuli, the increase of basal corticosterone secretion resulting from decreased anandamide allows for a facilitated response of the HPA axis to novel stimuli.

==== Exploration, social behavior, and anxiety ====
These contrasting effects reveal the importance of the endocannabinoid system in regulating [[anxiety]]-dependent behavior. Results suggest that glutamatergic cannabinoid receptors are not only responsible for mediating aggression, but produce an anxiolytic-like function by inhibiting excessive arousal: excessive excitation produces anxiety that limited the mice from exploring both animate and inanimate objects. In contrast, GABAergic neurons appear to control an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these two sets of neurons appear to help regulate the organism's overall sense of arousal during novel situations.<ref>{{cite journal | vauthors = Häring M, Kaiser N, Monory K, Lutz B | title = Circuit specific functions of cannabinoid CB1 receptor in the balance of investigatory drive and exploration | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e26617 | year = 2011 | pmid = 22069458 | pmc = 3206034 | doi = 10.1371/journal.pone.0026617 | veditors = Burgess HA | bibcode = 2011PLoSO...626617H | doi-access = free }}</ref>

=== Immune system ===

In laboratory experiments, activation of cannabinoid receptors had an effect on the activation of [[GTPase]]s in [[macrophage]]s, [[neutrophil]]s, and [[bone marrow]] cells. These receptors have also been implicated in the migration of [[B cell]]s into the [[marginal zone]] and the regulation of [[IgM]] levels.<ref>{{cite journal | vauthors = Basu S, Ray A, Dittel BN | title = Cannabinoid receptor 2 is critical for the homing and retention of marginal zone B lineage cells and for efficient T-independent immune responses | journal = The Journal of Immunology| volume = 187 | issue = 11 | pages = 5720–32 | date = December 2011 | pmid = 22048769 | pmc = 3226756 | doi = 10.4049/jimmunol.1102195 }}</ref>

=== Female reproduction ===
{{See also|Cannabis in pregnancy}}
The developing [[embryo]] expresses cannabinoid receptors early in development that are responsive to [[anandamide]] secreted in the [[uterus]]. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall. For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low.<ref>{{cite journal | vauthors = Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agrò A | s2cid = 39733100 | title = Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage | journal = Lancet | volume = 355 | issue = 9212 | pages = 1326–9 | year = 2000 | pmid = 10776746 | doi = 10.1016/S0140-6736(00)02115-2 }}</ref> These results suggest that intake of exogenous cannabinoids (e.g., [[cannabis]]) can decrease the likelihood for pregnancy for women with high anandamide levels, and alternatively, it can increase the likelihood for pregnancy in women whose anandamide levels were too low.<ref>{{cite journal | vauthors = Das SK, Paria BC, Chakraborty I, Dey SK | title = Cannabinoid ligand-receptor signaling in the mouse uterus | journal = Proceedings of the National Academy of Sciences| volume = 92 | issue = 10 | pages = 4332–6 | year = 1995 | pmid = 7753807 | pmc = 41938 | doi = 10.1073/pnas.92.10.4332 | bibcode = 1995PNAS...92.4332D | doi-access = free }}</ref><ref>{{cite journal | vauthors = Paria BC, Das SK, Dey SK | title = The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling | journal = Proceedings of the National Academy of Sciences| volume = 92 | issue = 21 | pages = 9460–4 | year = 1995 | pmid = 7568154 | pmc = 40821 | doi = 10.1073/pnas.92.21.9460 | bibcode = 1995PNAS...92.9460P | doi-access = free }}</ref>

=== Autonomic nervous system ===
Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the [[autonomic nervous system]]. Research found that the CB<sub>1</sub> receptor is expressed presynaptically by motor neurons that innervate visceral organs. Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from [[sympathetic nervous system]] nerves. Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems.<ref name="Elphick2001" />

=== Analgesia ===
At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending [[noradrenergic|noradrenaline]] input from the [[brainstem]].<ref name="Elphick2001" /> As many of these fibers are primarily [[GABA]]ergic, cannabinoid stimulation in the spinal column results in disinhibition that should increase noradrenaline release and attenuation of noxious-stimuli-processing in the periphery and [[dorsal root ganglion]].

The endocannabinoid most researched in pain is [[palmitoylethanolamide]]. Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the [[PPAR-alpha]] receptor, the [[TRPV]] receptor and the GPR55 receptor. Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications<ref>{{cite journal | vauthors = Hesselink JM | title = New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide | journal = The Open Pain Journal | year = 2012 | volume = 5 | issue = 1 | pages = 12–23 | doi = 10.2174/1876386301205010012 | doi-access = free }}</ref> and found to be safe and effective.

Modulation of the endocannabinoid system by metabolism to N-arachidinoyl-phenolamine (AM404), an endogenous cannabinoid neurotransmitter, has been discovered to be one [[Paracetamol#Pharmacodynamics|mechanism]]<ref name=Ghanem2016>{{cite journal|vauthors=Ghanem CI, Pérez MJ, Manautou JE, Mottino AD |title=Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity.|journal=Pharmacological Research|date=July 2016|volume=109|pages=119–31|doi=10.1016/j.phrs.2016.02.020|pmid=26921661|pmc=4912877}}</ref> for analgesia by acetaminophen (paracetamol).

Endocannabinoids are involved in [[placebo]] induced analgesia responses.<ref>{{cite book|last1=Colloca|first1=Luana | name-list-style = vanc |title=Placebo and Pain: From Bench to Bedside|date=28 August 2013|publisher=Elsevier Science|isbn=978-0-12-397931-5|pages=11–12|edition=1st}}</ref>

=== Thermoregulation ===
[[Anandamide]] and [[N-arachidonoyl dopamine|''N''-arachidonoyl dopamine]] (NADA) have been shown to act on temperature-sensing [[TRPV1]] channels, which are involved in thermoregulation.<ref name="pmid14517174">{{cite journal | vauthors = Ross RA | title = Anandamide and vanilloid TRPV1 receptors | journal = British Journal of Pharmacology| volume = 140 | issue = 5 | pages = 790–801 | date = November 2003 | pmid = 14517174 | pmc = 1574087 | doi = 10.1038/sj.bjp.0705467 }}</ref> TRPV1 is activated by the exogenous ligand [[capsaicin]], the active component of chili peppers, which is structurally similar to endocannabinoids. NADA activates the TRPV1 channel with {{clarify span|an [[EC50|EC<sub>50</sub>]] of approximately of 50&nbsp;nM.|date=January 2014}} The high potency makes it the putative endogenous TRPV1 agonist.<ref name="pmid12060783">{{cite journal | vauthors = Huang SM, Bisogno T, Trevisani M, Al-Hayani A, De Petrocellis L, Fezza F, Tognetto M, Petros TJ, Krey JF, Chu CJ, Miller JD, Davies SN, Geppetti P, Walker JM, Di Marzo V | title = An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors | journal = Proceedings of the National Academy of Sciences| volume = 99 | issue = 12 | pages = 8400–5 | date = June 2002 | pmid = 12060783 | pmc = 123079 | doi = 10.1073/pnas.122196999 | bibcode = 2002PNAS...99.8400H | doi-access = free }}</ref> Anandamide has also been found to activate TRPV1 on sensory neuron terminals, and subsequently cause [[vasodilation]].<ref name="Elphick2001" /> TRPV1 may also be activated by [[methanandamide]] and [[arachidonyl-2'-chloroethylamide]] (ACEA).<ref name="Pertwee2006" />

=== Sleep ===
Increased endocannabinoid signaling within the [[central nervous system]] promotes sleep-inducing effects. [[ventricular system|Intercerebroventricular]] administration of anandamide in rats has been shown to decrease wakefulness and increase [[slow-wave sleep]] and [[REM sleep]].<ref>{{cite journal | vauthors = Murillo-Rodríguez E, Sánchez-Alavez M, Navarro L, Martínez-González D, Drucker-Colín R, Prospéro-García O | s2cid = 23668458 | title = Anandamide modulates sleep and memory in rats | journal = Brain Research| volume = 812 | issue = 1–2 | pages = 270–4 | date = November 1998 | pmid = 9813364 | doi = 10.1016/S0006-8993(98)00969-X }}</ref> Administration of anandamide into the [[basal forebrain]] of rats has also been shown to increase levels of [[adenosine]], which plays a role in promoting sleep and suppressing arousal.<ref>{{cite journal | vauthors = Santucci V, Storme JJ, Soubrié P, Le Fur G | title = Arousal-enhancing properties of the CB1 cannabinoid receptor antagonist SR 141716A in rats as assessed by electroencephalographic spectral and sleep-waking cycle analysis | journal =Life Sciences| volume = 58 | issue = 6 | pages = PL103–10 | year = 1996 | pmid = 8569415 | doi = 10.1016/0024-3205(95)02319-4 }}</ref> REM sleep deprivation in rats has been demonstrated to increase CB1 receptor expression in the central nervous system.<ref>{{cite journal | vauthors = Wang L, Yang T, Qian W, Hou X | title = The role of endocannabinoids in visceral hyposensitivity induced by rapid eye movement sleep deprivation in rats: regional differences | journal = International Journal of Molecular Medicine| volume = 27 | issue = 1 | pages = 119–26 | date = January 2011 | pmid = 21057766 | doi = 10.3892/ijmm.2010.547 | doi-access = free }}</ref> Furthermore, anandamide levels possess a [[circadian rhythm]] in the rat, with levels being higher in the light phase of the day, which is when rats are usually asleep or less active, since they are [[nocturnal]].<ref>{{cite journal | vauthors = Murillo-Rodriguez E, Désarnaud F, Prospéro-García O | title = Diurnal variation of arachidonoylethanolamine, palmitoylethanolamide and oleoylethanolamide in the brain of the rat | journal = Life Sciences| volume = 79 | issue = 1 | pages = 30–7 | date = May 2006 | pmid = 16434061 | doi = 10.1016/j.lfs.2005.12.028 }}</ref>

=== Physical exercise ===

The endocannabinoid system is also involved in mediating some of the physiological and cognitive effects of voluntary [[physical exercise]] in humans and other animals, such as contributing to exercise-induced [[euphoria]] as well as modulating [[locomotor activity]] and [[motivational salience]] for [[reward system|rewards]].<ref name="endocannabinoids" /><ref name="Primary-Runner's high definition" /> In humans, the [[blood plasma|plasma]] concentration of certain endocannabinoids (i.e., [[anandamide]]) have been found to rise during physical activity;<ref name="endocannabinoids">{{cite journal | vauthors = Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M | s2cid = 14531019 | title = Physical activity and the endocannabinoid system: an overview | journal = Cellular and Molecular Life Sciences| volume = 71 | issue = 14 | pages = 2681–2698 | year = 2014 | pmid = 24526057 | doi = 10.1007/s00018-014-1575-6 | pmc = 11113821 }}</ref><ref name="Primary-Runner's high definition">{{cite journal | vauthors = Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A | title = Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high' | journal = Journal of Experimental Biology| volume = 215 | issue = Pt 8 | pages = 1331–1336 | year = 2012 | pmid = 22442371 | doi = 10.1242/jeb.063677 | doi-access = free }}</ref> since endocannabinoids can effectively penetrate the [[blood–brain barrier]], it has been suggested that anandamide, along with other [[euphoriant]] neurochemicals, contributes to the development of exercise-induced euphoria in humans, a state colloquially referred to as a [[Neurobiological effects of physical exercise#Euphoria|runner's high]].<ref name="endocannabinoids" /><ref name="Primary-Runner's high definition" />

== Cannabinoids in plants ==

The endocannabinoid system is by [[Molecular biology|molecular]] [[Phylogenetics|phylogenetic]] distribution of apparently ancient lipids in the [[plant]] kingdom, indicative of [[Biosynthesis|biosynthetic]] [[Neuroplasticity|plasticity]] and potential [[Physiological plant disorder|physiological]] roles of endocannabinoid-like lipids in plants,<ref>{{cite journal | vauthors = Gachet MS, Schubert A, Calarco S, Boccard J, Gertsch J | title = Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom | journal = Scientific Reports | volume = 7 | pages = 41177 | date = January 2017 | pmid = 28120902 | pmc = 5264637 | doi = 10.1038/srep41177 | bibcode = 2017NatSR...741177G }}</ref> and detection of [[arachidonic acid]] (AA) indicates [[Chemotaxonomy|chemotaxonomic]] connections between [[Monophyly|monophyletic]] groups with common ancestor dates to around 500 million years ago ([[Cambrian]]). The phylogenetic distribution of these lipids may be a consequence of interactions/adaptations to the surrounding conditions such as [[Chemical substance|chemical]] plant-pollinator interactions, [[Plant communication|communication]] and [[Plant defense against herbivory|defense]] mechanisms. The two novel EC-like molecules derived from the [[eicosatetraenoic acid]] [[juniperonic acid]], an [[Omega-3 fatty acid|omega-3]] structural [[isomer]] of AA, namely juniperoyl ethanolamide and 2-juniperoyl glycerol (1/2-AG) in [[gymnosperm]]s, [[Lycopodiophyta|lycophytes]] and few [[Fern|monilophytes]], show AA is an [[evolution]]arily conserved [[Cell signaling|signalling molecule]] that acts in plants in response to [[Stress (biology)|stress]] similar to that in [[animal]] systems.<ref>{{cite journal | vauthors = Wasternack C, Hause B | title = Jasmonates: biosynthesis, perception, signal transduction and action in plant stress response, growth and development. An update to the 2007 review in Annals of Botany | journal = Annals of Botany | volume = 111 | issue = 6 | pages = 1021–58 | date = June 2013 | pmid = 23558912 | pmc = 3662512 | doi = 10.1093/aob/mct067 }}</ref> The endocannabinoid [[Docosatetraenoylethanolamide]] has been found in ''[[Tropaeolum tuberosum]]'' (''mashua'') and ''[[Leonotis leonurus]]'' (lion's tail).<ref>{{cite journal | doi=10.1186/s13104-020-05372-z | title=Toward the identification of a phytocannabinoid-like compound in the flowers of a South African medicinal plant (Leonotis leonurus) | year=2020 | last1=Hunter | first1=E. | last2=Stander | first2=M. | last3=Kossmann | first3=J. | last4=Chakraborty | first4=S. | last5=Prince | first5=S. | last6=Peters | first6=S. | last7=Loedolff | first7=Bianke | journal=BMC Research Notes | volume=13 | issue=1 | page=522 | pmid=33172494 | pmc=7653773 | doi-access=free }}</ref> Maca contains several N-benzylamides referred to as "macamides" that are structurally related to endocannabinoids such as the N-Benzyl analog of [[oleamide]].<ref>{{cite journal | url=https://www.sciencedirect.com/science/article/abs/pii/S0963996920308449 | doi=10.1016/j.foodres.2020.109819 | title=Macamides: A review of structures, isolation, therapeutics and prospects | year=2020 | last1=Zhu | first1=Hongkang | last2=Hu | first2=Bin | last3=Hua | first3=Hanyi | last4=Liu | first4=Chang | last5=Cheng | first5=Yuliang | last6=Guo | first6=Yahui | last7=Yao | first7=Weirong | last8=Qian | first8=He | journal=Food Research International | volume=138 | issue=Pt B | page=109819 | pmid=33288191 | s2cid=226344133 | url-access=subscription }}</ref> [[Echinacea]] contains alkylamides structurally related to endocannabinoids.<ref>{{cite journal | url=https://pubs.acs.org/doi/10.1021/jf201158k | doi=10.1021/jf201158k | title=Analysis of Alkylamides in Echinacea Plant Materials and Dietary Supplements by Ultrafast Liquid Chromatography with Diode Array and Mass Spectrometric Detection | year=2011 | last1=Mudge | first1=Elizabeth | last2=Lopes-Lutz | first2=Daise | last3=Brown | first3=Paula | last4=Schieber | first4=Andreas | journal=Journal of Agricultural and Food Chemistry | volume=59 | issue=15 | pages=8086–8094 | pmid=21702479 | url-access=subscription }}</ref>

== Cannabinoids in Cyanobacterium ==
[[Serinolamide A]] is a cannabinoid structurally related to endocannabinoids found in [[cyanobacteria]] such as [[Lyngbya majuscula]] and other species in the [[Oscillatoria]] family.

== Endocannabinoid articles ==
* [[Anandamide]]
* [[2-Arachidonoylglycerol]]
* [[2-Arachidonyl glyceryl ether]]
* [[Oleamide]]
* [[Oleoylethanolamide]]
* [[Virodhamine]]
* [[Docosatetraenoylethanolamide]]
* [[Stearoylethanolamide]]
* [[N-Arachidonylglycine]]
* [[Arachidonoyl serotonin]]
* [[N-Arachidonoyl dopamine]]
* [[N-Acylethanolamine|''N''-Acylethanolamine]]

== See also ==
* [[Endocannabinoid enhancer]]
* [[Endocannabinoid reuptake inhibitor]]
* [[Cannabinol]]
* [[Cannabinoid receptor antagonist]]
* [[Jasmonate]]
* [[Peroxisome proliferator-activated receptor]]
* [[TRPV]]

== References ==
{{reflist|30em}}

== External links ==
* [http://www.cannabinoidsociety.org/ Homepage of the ICRS] – The International Cannabinoid Research Society
{{Commonscat}}{{Wiktionary}}{{Cannabis}}
{{Cannabinoid receptor modulators}}
{{Transient receptor potential channel modulators}}

[[Category:Neurochemistry]]
[[Category:Endocannabinoids| ]]