The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system (including the brain) and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, during pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis.
Two primary cannabinoid receptors have been identified: CB1, first cloned 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 (AEA), as well as exogenous THC, the most known active component of cannabis. Endocannabinoid 2-arachidonoylglycerol (2-AG), which is 170-fold more abundant in brain than AEA, acts as a full agonist at both CBRs. CBD is a phytocannabinoid that acts as a rather weak antagonist at both CBRs and a more potent agonist at TRPV1 and antagonist at TRPM8. It is also known to be a negative allosteric modulator at CB1. CBD has been found to counteract some of the negative side effects of THC.
The endocannabinoid system, broadly speaking, includes:
- The endogenous arachidonate-based lipids, anandamide (N-arachidonoylethanolamide) and 2-AG; these are known as "endocannabinoids" and are physiological ligands for the cannabinoid receptors. Endocannabinoids are all eicosanoids.
- The enzymes that synthesize and degrade the endocannabinoids, such as fatty acid amide hydrolase or monoacylglycerol lipase.
- The cannabinoid receptors CB1 and CB2, two G protein-coupled receptors that are located in the central and peripheral nervous systems.
The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that cannabinoids act as neuromodulators for a variety of processes, including motor learning, appetite, and pain sensation, among other cognitive and physical processes. The localization of the CB1 receptor in the endocannabinoid system has a very large degree of overlap with the orexinergic projection system, which mediates many of the same functions, both physical and cognitive. Moreover, CB1 is colocalized on orexin projection neurons in the lateral hypothalamus and many output structures of the orexin system, where the CB1 and orexin receptor 1 (OX1) receptors physically and functionally join together to form the CB1–OX1 receptor heterodimer.
Expression of receptors
Cannabinoid binding sites exist throughout the central and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB1 and CB2 receptors, which are expressed predominantly in the brain and immune system respectively. 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. 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 CB1 and CB2 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. 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.
In addition to CB1 and CB2, certain orphan receptors are known to bind endocannabinoids as well, including GPR18, GPR55 (a regulator of neuroimmune function), and GPR119. CB1 has also been noted to form a functional human receptor heterodimer in orexin neurons with OX1, the CB1–OX1 receptor, which mediates feeding behavior and certain physical processes such as cannabinoid-induced pressor responses which are known to occur through signaling in the rostral ventrolateral medulla.
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 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. 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 mGluR1/5 receptors triggered the synthesis of anandamide.
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 (NAPE). Experiments have shown that phospholipase D cleaves NAPE to yield anandamide. This process is mediated by bile acids. 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. 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. 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. 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. 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.
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 CB1 receptors to an acute rise in cyclic adenosine monophosphate (cAMP) production, it is generally accepted that CB1 activation via cannabinoids causes a decrease in cAMP concentration by inhibition of adenylyl cyclase and a rise in the concentration of mitogen-activated protein kinase (MAP kinase). 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/p42/p44), but also the PI3/PKB and MEK/ERK pathway. 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 RNAs. In addition, CB1 activation has been demonstrated to increase the activity of transcription factors like c-Fos and Krox-24.
Binding and neuronal excitability
The molecular mechanisms of CB1-mediated changes to the membrane voltage have also been studied in detail. Cannabinoids reduce calcium influx by blocking the activity of voltage-dependent N-, P/Q- and L-type calcium channels. In addition to acting on calcium channels, activation of Gi/o and Gs, the two most commonly coupled G-proteins to cannabinoid receptors, has been shown to modulate potassium channel activity. Recent studies have found that CB1 activation specifically facilitates potassium ion flux through GIRKs, a family of potassium channels. Immunohistochemistry experiments demonstrated that CB1 is co-localized with GIRK and Kv1.4 potassium channels, suggesting that these two may interact in physiological contexts.
In the central nervous system, CB1 receptors influence neuronal excitability, reducing the incoming synaptic input. 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. CB1 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 CB1 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. Direct effects of CB1 receptors on membrane excitability have been reported, and strongly impact the firing of cortical neurons. A series of behavioral experiments demonstrated that NMDAR, an ionotropic glutamate receptor, and the metabotropic glutamate receptors (mGluRs) work in concert with CB1 to induce analgesia in mice, although the mechanism underlying this effect is unclear.
Mice treated with tetrahydrocannabinol (THC) show suppression of long-term potentiation in the hippocampus, a process that is essential for the formation and storage of long-term memory. These results may concur with anecdotal evidence suggesting that smoking cannabis impairs short-term memory. Consistent with this finding, mice without the CB1 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 region, a part of the limbic system playing a part in the formation of declarative and spatial memories, but did not investigate the effects on short-term or long-term memory. 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. In the subgranular zone of the dentate gyrus, multipotent neural progenitors (NP) give rise to daughter cells that, over the course of several weeks, mature into granule cells whose axons project to and synapse onto dendrites on the CA3 region. NPs in the hippocampus have been shown to possess fatty acid amide hydrolase (FAAH) and express CB1 and utilize 2-AG. Intriguingly, CB1 activation by endogenous or exogenous cannabinoids promote NP proliferation and differentiation; this activation is absent in CB1 knockouts and abolished in the presence of antagonist.
Induction of synaptic depression
Endocannabinoids are known to influence synaptic plasticity, and are in particular thought to mediate long-term depression (LTD), although short-term depression (STD) has also been described (see the next paragraph). First reported in the striatum, 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. Typically, these retrograde transmitters are released by the postsynaptic neuron and induce synaptic depression by activating the presynaptic CB1 receptors.
It has further been suggested that different endocannabinoids, i.e. 2-AG and anandamide, might mediate different forms of synaptic depression through different mechanisms. The study conducted with the 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 CB1 receptors to mediate retrograde STD following activation of L-type calcium channeles, while anandamide was synthesized after mGluR5 activation and triggered autocrine signalling onto postsynapic TRPV1 receptors that induced LTD. 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.
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 CB1 receptors in the hypothalamic nuclei to directly increase appetite. 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. For example, mice without leptin not only become massively obese but express abnormally high levels of hypothalamic endocannabinoids as a compensatory mechanism. Similarly, when these mice were treated with an endocannabinoid inverse agonists, such as rimonabant, food intake was reduced. When the CB1 receptor is 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. A related study found that endocannabinoids affect taste perception in taste cells 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.
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.
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 CB1 antagonist AM251, supporting the conclusion that these effects were cannabinoid-receptor dependent. 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.
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.
In laboratory experiments, activation of cannabinoid receptors had an effect on the activation of GTPases in macrophages, neutrophils, and bone marrow cells. These receptors have also been implicated in the migration of B cells into the marginal zone and the regulation of IgM levels.
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. 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.
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 CB1 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.
At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending noradrenaline input from the brainstem. As many of these fibers are primarily GABAergic, 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 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 mechanism for analgesia by acetaminophen (paracetamol).
Anandamide and N-arachidonoyl dopamine (NADA) have been shown to act on temperature-sensing TRPV1 channels, which are involved in thermoregulation. 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] The high potency makes it the putative endogenous TRPV1 agonist. Anandamide has also been found to activate TRPV1 on sensory neuron terminals, and subsequently cause vasodilation. TRPV1 may also be activated by methanandamide and arachidonyl-2'-chloroethylamide (ACEA).
Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects. Intercerebroventricular administration of anandamide in rats has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep. 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. REM sleep deprivation in rats has been demonstrated to increase CB1 receptor expression in the central nervous system. 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.
Anandamide is an endogenous cannabinoid neurotransmitter that binds to cannabinoid receptors. The ECS 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 rewards. In humans, the plasma concentration of certain endocannabinoids (i.e., anandamide) have been found to rise during physical activity; 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 runner's high.
Cannabinoids in plants
The endocannabinoid system is by molecular phylogenetic distribution of apparently ancient lipids in the plant kingdom, indicative of biosynthetic plasticity and potential physiological roles of endocannabinoid-like lipids in plants, and detection of arachidonic acid (AA) indicates chemotaxonomic connections between monophyletic groups with common ancestor dates to around 500 million years ago (Silurian; Devonian). The phylogenetic distribution of these lipids may be a consequence of interactions/adaptations to the surrounding conditions such as chemical plant-pollinator interactions, communication and defense mechanisms. The two novel EC-like molecules derived from the eicosatetraenoic acid juniperonic acid, an omega-3 structural isomer of AA, namely juniperoyl ethanolamide and 2-juniperoyl glycerol (1/2-AG) in gymnosperms, lycophytes and few monilophytes, show AA is an evolutionarily conserved signalling molecule that acts in plants in response to stress similar to that in animal systems.
- Endocannabinoid enhancer
- Endocannabinoid reuptake inhibitor
- Cannabinoid receptor antagonist
- 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.
- 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.
- 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.
- 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. PMID 29751000.
- De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, et al. (August 2011). "Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes". British Journal of Pharmacology. 163 (7): 1479–94. doi:10.1111/j.1476-5381.2010.01166.x. PMC 3165957. PMID 21175579.
- Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM (October 2015). "Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor". British Journal of Pharmacology. 172 (20): 4790–805. doi:10.1111/bph.13250. PMC 4621983. PMID 26218440.
- Hudson R, Renard J, Norris C, Rushlow WJ, Laviolette SR (October 2019). "Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus through Bidirectional Control of ERK1-2 Phosphorylation". The Journal of Neuroscience. 39 (44): 8762–8777. doi:10.1523/JNEUROSCI.0708-19.2019. PMC 6820200. PMID 31570536.
- Pertwee RG (April 2006). "The pharmacology of cannabinoid receptors and their ligands: an overview". International Journal of Obesity. 30 (Suppl 1): S13–8. doi:10.1038/sj.ijo.0803272. PMID 16570099.
- Fortin DA, Levine ES (2007). "Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons". Cerebral Cortex. 17 (1): 163–74. doi:10.1093/cercor/bhj133. PMID 16467564.
- Good CH (2007). "Endocannabinoid-dependent regulation of feedforward inhibition in cerebellar Purkinje cells". Journal of Neuroscience. 27 (1): 1–3. doi:10.1523/JNEUROSCI.4842-06.2007. PMC 6672293. PMID 17205618.
- Hashimotodani Y, Ohno-Shosaku T, Kano M (2007). "Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus". Journal of Neuroscience. 27 (5): 1211–9. doi:10.1523/JNEUROSCI.4159-06.2007. PMC 6673197. PMID 17267577.
- Kishimoto Y, Kano M (2006). "Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning". Journal of Neuroscience. 26 (34): 8829–37. doi:10.1523/JNEUROSCI.1236-06.2006. PMC 6674369. PMID 16928872.
- Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G (April 2001). "Leptin-regulated endocannabinoids are involved in maintaining food intake". Nature. 410 (6830): 822–5. Bibcode:2001Natur.410..822D. doi:10.1038/35071088. PMID 11298451.
- Cravatt BF, et al. (July 2001). "Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase". Proceedings of the National Academy of Sciences. 98 (16): 9371–6. Bibcode:2001PNAS...98.9371C. doi:10.1073/pnas.161191698. JSTOR 3056353. PMC 55427. PMID 11470906.
- Flores A, Maldonado R, Berrendero F (2013). "Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far". Frontiers in Neuroscience. 7: 256. doi:10.3389/fnins.2013.00256. PMC 3868890. PMID 24391536.
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 ... 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. ... 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.
• Figure 1: Schematic of brain CB1 expression and orexinergic neurons expressing OX1 or OX2
• Figure 2: Synaptic signaling mechanisms in cannabinoid and orexin systems
• Figure 3: Schematic of brain pathways involved in food intake
- Watkins BA, Kim J (2014). "The endocannabinoid system: helps to direct eating behavior and macronutrient metabolism". Frontiers in Psychology. 5: 1506. doi:10.3389/fpsyg.2014.01506. PMC 4285050. PMID 25610411.
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. ... 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). ... 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).
- Thompson MD, Xhaard H, Sakurai T, Rainero I, Kukkonen JP (2014). "OX1 and OX2 orexin/hypocretin receptor pharmacogenetics". Frontiers in Neuroscience. 8: 57. doi:10.3389/fnins.2014.00057. PMC 4018553. PMID 24834023.
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.
- Jäntti MH, Mandrika I, Kukkonen JP (2014). "Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors". Biochemical and Biophysical Research Communications. 445 (2): 486–90. doi:10.1016/j.bbrc.2014.02.026. PMID 24530395.
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. ... 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.
- Pertwee RG (January 2008). "The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin". British Journal of Pharmacology. 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC 2219532. PMID 17828291.
- Elphick MR, Egertová M (March 2001). "The neurobiology and evolution of cannabinoid signalling". Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences. 356 (1407): 381–408. doi:10.1098/rstb.2000.0787. PMC 1088434. PMID 11316486.
- Puente N, Cui Y, Lassalle O, Lafourcade M, Georges F, Venance L, Grandes P, Manzoni OJ (December 2011). "Polymodal activation of the endocannabinoid system in the extended amygdala". Nature Neuroscience. 14 (12): 1542–7. doi:10.1038/nn.2974. PMID 22057189.
- Ibrahim BM, Abdel-Rahman AA (2014). "Cannabinoid receptor 1 signaling in cardiovascular regulating nuclei in the brainstem: A review". Journal of Advanced Research. 5 (2): 137–45. doi:10.1016/j.jare.2013.03.008. PMC 4294710. PMID 25685481.
- Ibrahim BM, Abdel-Rahman AA (2015). "A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats". Brain Research. 1622: 51–63. doi:10.1016/j.brainres.2015.06.011. PMC 4562882. PMID 26096126.
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 ... 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
- Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (February 2004). "Molecular characterization of a phospholipase D generating anandamide and its congeners". Journal of Biological Chemistry. 279 (7): 5298–305. doi:10.1074/jbc.M306642200. PMID 14634025.
- Liu J, Wang L, Harvey-White J, Osei-Hyiaman D, Razdan R, Gong Q, Chan AC, Zhou Z, Huang BX, Kim HY, Kunos G (September 2006). "A biosynthetic pathway for anandamide". Proceedings of the National Academy of Sciences. 103 (36): 13345–50. Bibcode:2006PNAS..10313345L. doi:10.1073/pnas.0601832103. PMC 1557387. PMID 16938887.
- Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, Garau G (2014). "Structure of Human N-Acylphosphatidylethanolamine-Hydrolyzing Phospholipase D: Regulation of Fatty Acid Ethanolamide Biosynthesis by Bile Acids". Structure. 23 (3): 598–604. doi:10.1016/j.str.2014.12.018. PMC 4351732. PMID 25684574.
- Margheritis E, Castellani B, Magotti P, Peruzzi S, Romeo E, Natali F, Mostarda S, Gioiello A, Piomelli D, Garau G (2016). "Bile Acid Recognition by NAPE-PLD". ACS Chemical Biology. 11 (10): 2908–2914. doi:10.1021/acschembio.6b00624. PMC 5074845. PMID 27571266.
- Leung D, Saghatelian A, Simon GM, Cravatt BF (April 2006). "Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids". Biochemistry. 45 (15): 4720–6. doi:10.1021/bi060163l. PMC 1538545. PMID 16605240.
- Pazos MR, Núñez E, Benito C, Tolón RM, Romero J (June 2005). "Functional neuroanatomy of the endocannabinoid system". Pharmacology Biochemistry and Behavior. 81 (2): 239–47. doi:10.1016/j.pbb.2005.01.030. PMID 15936805.
- Yamaguchi T, Shoyama Y, Watanabe S, Yamamoto T (January 2001). "Behavioral suppression induced by cannabinoids is due to activation of the arachidonic acid cascade in rats". Brain Research. 889 (1–2): 149–54. doi:10.1016/S0006-8993(00)03127-9. PMID 11166698.
- Brock TG (December 2005). "Regulating leukotriene synthesis: the role of nuclear 5-lipoxygenase" (PDF). Journal of Cellular Biochemistry. 96 (6): 1203–11. doi:10.1002/jcb.20662. hdl:2027.42/49282. PMID 16215982.
- Clapper JR, Mangieri RA, Piomelli D (2009). "The endocannabinoid system as a target for the treatment of cannabis dependence". Neuropharmacology. 56 (Suppl 1): 235–43. doi:10.1016/j.neuropharm.2008.07.018. PMC 2647947. PMID 18691603.
- Galve-Roperh I, Rueda D, Gómez del Pulgar T, Velasco G, Guzmán M (December 2002). "Mechanism of extracellular signal-regulated kinase activation by the CB(1) cannabinoid receptor". Molecular Pharmacology. 62 (6): 1385–92. doi:10.1124/mol.62.6.1385. PMID 12435806.
- Graham ES, Ball N, Scotter EL, Narayan P, Dragunow M, Glass M (September 2006). "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". The Journal of Biological Chemistry. 281 (39): 29085–95. doi:10.1074/jbc.M602516200. PMID 16864584.
- Kittler JT, Grigorenko EV, Clayton C, Zhuang SY, Bundey SC, Trower MM, Wallace D, Hampson R, Deadwyler S (September 2000). "Large-scale analysis of gene expression changes during acute and chronic exposure to [Delta]9-THC in rats". Physiological Genomics. 3 (3): 175–85. doi:10.1152/physiolgenomics.2000.3.3.175. PMID 11015613.
- Twitchell W, Brown S, Mackie K (1997). "Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons". Journal of Neurophysiology. 78 (1): 43–50. doi:10.1152/jn.19220.127.116.11. PMID 9242259.
- Guo J, Ikeda SR (2004). "Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons". Molecular Pharmacology. 65 (3): 665–74. doi:10.1124/mol.65.3.665. PMID 14978245.
- Binzen U, Greffrath W, Hennessy S, Bausen M, Saaler-Reinhardt S, Treede RD (2006). "Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons". Neuroscience. 142 (2): 527–39. doi:10.1016/j.neuroscience.2006.06.020. PMID 16889902.
- Freund TF, Katona I, Piomelli D (2003). "Role of endogenous cannabinoids in synaptic signaling". Physiological Reviews. 83 (3): 1017–66. doi:10.1152/physrev.00004.2003. PMID 12843414.
- Chevaleyre V, Heifets BD, Kaeser PS, Südhof TC, Purpura DP, Castillo PE (2007). "Endocannabinoid-Mediated Long-Term Plasticity Requires cAMP/PKA Signaling and RIM1α". Neuron. 54 (5): 801–12. doi:10.1016/j.neuron.2007.05.020. PMC 2001295. PMID 17553427.
- Bacci A, Huguenard JR, Prince DA (2004). "Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids". Nature. 431 (7006): 312–6. Bibcode:2004Natur.431..312B. doi:10.1038/nature02913. PMID 15372034.
- Hampson RE, Deadwyler SA (1999). "Cannabinoids, hippocampal function and memory". Life Sciences. 65 (6–7): 715–23. doi:10.1016/S0024-3205(99)00294-5. PMID 10462072.
- Pertwee RG (2001). "Cannabinoid receptors and pain". Progress in Neurobiology. 63 (5): 569–611. doi:10.1016/S0301-0082(00)00031-9. PMID 11164622.
- Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X (2005). "Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects". Journal of Clinical Investigation. 115 (11): 3104–16. doi:10.1172/JCI25509. PMC 1253627. PMID 16224541.
- Aguado T, Monory K, Palazuelos J, Stella N, Cravatt B, Lutz B, Marsicano G, Kokaia Z, Guzmán M, Galve-Roperh I (2005). "The endocannabinoid system drives neural progenitor proliferation". The FASEB Journal. 19 (12): 1704–6. doi:10.1096/fj.05-3995fje. PMID 16037095.
- Christie BR, Cameron HA (2006). "Neurogenesis in the adult hippocampus". Hippocampus. 16 (3): 199–207. doi:10.1002/hipo.20151. PMID 16411231.
- Gerdeman GL, Ronesi J, Lovinger DM (May 2002). "Postsynaptic endocannabinoid release is critical to long-term depression in the striatum". Nature Neuroscience. 5 (5): 446–51. doi:10.1038/nn832. PMID 11976704.
- Heifets BD, Castillo PE (12 February 2009). "Endocannabinoid signaling and long-term synaptic plasticity". Annual Review of Physiology. 71 (1): 283–306. doi:10.1146/annurev.physiol.010908.163149. PMC 4454279. PMID 19575681.
- Kirkham TC, Tucci SA (2006). "Endocannabinoids in appetite control and the treatment of obesity". CNS Neurol Disord Drug Targets. 5 (3): 272–92. doi:10.2174/187152706777452272. PMID 16787229.
- Di Marzo V, Sepe N, De Petrocellis L, Berger A, Crozier G, Fride E, Mechoulam R (December 1998). "Trick or treat from food endocannabinoids?". Nature. 396 (6712): 636–7. Bibcode:1998Natur.396..636D. doi:10.1038/25267. PMID 9872309.
- De Luca MA, Solinas M, Bimpisidis Z, Goldberg SR, Di Chiara G (July 2012). "Cannabinoid facilitation of behavioral and biochemical hedonic taste responses". Neuropharmacology. 63 (1): 161–8. doi:10.1016/j.neuropharm.2011.10.018. PMC 3705914. PMID 22063718.
- Yoshida R, et al. (January 2010). "Endocannabinoids selectively enhance sweet taste". Proceedings of the National Academy of Sciences. 107 (2): 935–9. Bibcode:2010PNAS..107..935Y. doi:10.1073/pnas.0912048107. JSTOR 40535875. PMC 2818929. PMID 20080779.
- Bellocchio L, Cervino C, Pasquali R, Pagotto U (June 2008). "The endocannabinoid system and energy metabolism". Journal of Neuroendocrinology. 20 (6): 850–7. doi:10.1111/j.1365-2826.2008.01728.x. PMID 18601709.
- Hill MN, McLaughlin RJ, Bingham B, Shrestha L, Lee TT, Gray JM, Hillard CJ, Gorzalka BB, Viau V (May 2010). "Endogenous cannabinoid signaling is essential for stress adaptation". Proceedings of the National Academy of Sciences. 107 (20): 9406–11. Bibcode:2010PNAS..107.9406H. doi:10.1073/pnas.0914661107. PMC 2889099. PMID 20439721.
- Häring M, Kaiser N, Monory K, Lutz B (2011). Burgess HA (ed.). "Circuit specific functions of cannabinoid CB1 receptor in the balance of investigatory drive and exploration". PLOS ONE. 6 (11): e26617. Bibcode:2011PLoSO...626617H. doi:10.1371/journal.pone.0026617. PMC 3206034. PMID 22069458.
- Basu S, Ray A, Dittel BN (December 2011). "Cannabinoid receptor 2 is critical for the homing and retention of marginal zone B lineage cells and for efficient T-independent immune responses". The Journal of Immunology. 187 (11): 5720–32. doi:10.4049/jimmunol.1102195. PMC 3226756. PMID 22048769.
- Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agrò A (2000). "Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage". Lancet. 355 (9212): 1326–9. doi:10.1016/S0140-6736(00)02115-2. PMID 10776746.
- Das SK, Paria BC, Chakraborty I, Dey SK (1995). "Cannabinoid ligand-receptor signaling in the mouse uterus". Proceedings of the National Academy of Sciences. 92 (10): 4332–6. Bibcode:1995PNAS...92.4332D. doi:10.1073/pnas.92.10.4332. PMC 41938. PMID 7753807.
- Paria BC, Das SK, Dey SK (1995). "The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling". Proceedings of the National Academy of Sciences. 92 (21): 9460–4. Bibcode:1995PNAS...92.9460P. doi:10.1073/pnas.92.21.9460. PMC 40821. PMID 7568154.
- Hesselink JM (2012). "New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide". The Open Pain Journal. 5 (1): 12–23. doi:10.2174/1876386301205010012.
- Ghanem CI, Pérez MJ, Manautou JE, Mottino AD (July 2016). "Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity". Pharmacological Research. 109: 119–31. doi:10.1016/j.phrs.2016.02.020. PMC 4912877. PMID 26921661.
- Colloca, Luana (28 August 2013). Placebo and Pain: From Bench to Bedside (1st ed.). Elsevier Science. pp. 11–12. ISBN 978-0-12-397931-5.
- Ross RA (November 2003). "Anandamide and vanilloid TRPV1 receptors". British Journal of Pharmacology. 140 (5): 790–801. doi:10.1038/sj.bjp.0705467. PMC 1574087. PMID 14517174.
- 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 (June 2002). "An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors". Proceedings of the National Academy of Sciences. 99 (12): 8400–5. Bibcode:2002PNAS...99.8400H. doi:10.1073/pnas.122196999. PMC 123079. PMID 12060783.
- Murillo-Rodríguez E, Sánchez-Alavez M, Navarro L, Martínez-González D, Drucker-Colín R, Prospéro-García O (November 1998). "Anandamide modulates sleep and memory in rats". Brain Research. 812 (1–2): 270–4. doi:10.1016/S0006-8993(98)00969-X. PMID 9813364.
- Santucci V, Storme JJ, Soubrié P, Le Fur G (1996). "Arousal-enhancing properties of the CB1 cannabinoid receptor antagonist SR 141716A in rats as assessed by electroencephalographic spectral and sleep-waking cycle analysis". Life Sciences. 58 (6): PL103–10. doi:10.1016/0024-3205(95)02319-4. PMID 8569415.
- Wang L, Yang T, Qian W, Hou X (January 2011). "The role of endocannabinoids in visceral hyposensitivity induced by rapid eye movement sleep deprivation in rats: regional differences". International Journal of Molecular Medicine. 27 (1): 119–26. doi:10.3892/ijmm.2010.547. PMID 21057766.
- Murillo-Rodriguez E, Désarnaud F, Prospéro-García O (May 2006). "Diurnal variation of arachidonoylethanolamine, palmitoylethanolamide and oleoylethanolamide in the brain of the rat". Life Sciences. 79 (1): 30–7. doi:10.1016/j.lfs.2005.12.028. PMID 16434061.
- Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M (2014). "Physical activity and the endocannabinoid system: an overview". Cellular and Molecular Life Sciences. 71 (14): 2681–2698. doi:10.1007/s00018-014-1575-6. PMID 24526057.
- Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A (2012). "Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high'". Journal of Experimental Biology. 215 (Pt 8): 1331–1336. doi:10.1242/jeb.063677. PMID 22442371.
- Gachet MS, Schubert A, Calarco S, Boccard J, Gertsch J (January 2017). "Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom". Scientific Reports. 7: 41177. Bibcode:2017NatSR...741177G. doi:10.1038/srep41177. PMC 5264637. PMID 28120902.
- Wasternack C, Hause B (June 2013). "Jasmonates: biosynthesis, perception, signal transduction and action in plant stress response, growth and development. An update to the 2007 review in Annals of Botany". Annals of Botany. 111 (6): 1021–58. doi:10.1093/aob/mct067. PMC 3662512. PMID 23558912.
- Homepage of the ICRS – The International Cannabinoid Research Society