Endocannabinoid system

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3D model of 2-Arachidonoylglycerol, an endocannaboid

The endocannabinoid system (ECS) is a biological system composed of

pharmacological effects of cannabis.[9][10] The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.[11]

Two primary cannabinoid receptors have been identified:

2-arachidonoylglycerol (2-AG), which was found to be two and three orders of magnitude more abundant in mammalian brain than anandamide, acts as a full agonist at both CB receptors.[12]

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

Basic overview

The endocannabinoid system, broadly speaking, includes:

The

neurons, neural pathways, and other cells where these molecules, enzymes, and one or both cannabinoid receptor types are all colocalized
collectively comprise the endocannabinoid system.

The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that

orexin receptor 1 (OX1) receptors physically and functionally join to form the CB1–OX1 receptor heterodimer.[24][26][27]

Expression of receptors

Further information on receptor localization:
Cannabinoid receptor type 2 (CB2)

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.[28] 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.[29] 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

2-arachidonoylglycerol (2-AG) on the TRPV1 receptor suggesting that this receptor may be a candidate for the established response.[30]

In addition to CB1 and CB2, certain

pressor responses which are known to occur through signaling in the rostral ventrolateral medulla.[31][32]

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.[28] 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.[30]

Evidence suggests that the depolarization-induced influx of calcium into the post-synaptic neuron causes the activation of an enzyme called

bile acids.[35][36]
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.[37]
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

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.[38] 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.[39][40] 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.[29] 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.[41]

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

Krox-24.[44]

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

GIRKs, a family of potassium channels.[47] Immunohistochemistry experiments demonstrated that CB1 is co-localized with GIRK and Kv1.4 potassium channels, suggesting that these two may interact in physiological contexts.[48]

In the central nervous system, CB1 receptors influence neuronal excitability, reducing the incoming synaptic input.[49] 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.[50] Direct effects of CB1 receptors on membrane excitability have been reported, and strongly impact the firing of cortical neurons.[51] A series of behavioral experiments demonstrated that

analgesia in mice, although the mechanism underlying this effect is unclear.[citation needed
]

Potential functions

Memory

Mice treated with

declarative and spatial memories, but did not investigate the effects on short-term or long-term memory.[54]
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

CA3 region.[56] NPs in the hippocampus have been shown to possess fatty acid amide hydrolase (FAAH) and express CB1 and utilize 2-AG.[55] 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.[54][55]

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). Short-term depression (STD) has also been described (see the next paragraph). First reported in the striatum,[57] 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.[58] Typically, these retrograde transmitters are released by the postsynaptic neuron and induce synaptic depression by activating the presynaptic CB1 receptors.[58]

It has further been suggested that different endocannabinoids, i.e., 2-AG and anandamide, might mediate different forms of synaptic depression through different mechanisms.

autocrine signalling onto postsynapic TRPV1 receptors that induced LTD.[30]
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 CB1 receptors in the hypothalamic nuclei to directly increase appetite.[59] 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.[60] For example, mice without leptin not only become massively obese but express abnormally high levels of hypothalamic endocannabinoids as a compensatory mechanism.[22] Similarly, when these mice were treated with an endocannabinoid inverse agonists, such as rimonabant, food intake was reduced.[22] 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.[61] A related study found that endocannabinoids affect taste perception in taste cells.[62] 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.[59]

Energy balance and metabolism

The endocannabinoid system has been shown to have a

cardiovascular role.[63]

Stress response

While the secretion of

AM251, supporting the conclusion that these effects were cannabinoid-receptor dependent.[64]
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.[65]

Immune system

In laboratory experiments, activation of cannabinoid receptors had an effect on the activation of

IgM levels.[66]

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.[67] 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.[68][69]

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.[29]

Analgesia

At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending

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

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[70]
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[71] for analgesia by acetaminophen (paracetamol).

Endocannabinoids are involved in placebo induced analgesia responses.[72]

Thermoregulation

N-arachidonoyl dopamine (NADA) have been shown to act on temperature-sensing TRPV1 channels, which are involved in thermoregulation.[73] 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 an EC50 of approximately of 50 nM.[clarify] The high potency makes it the putative endogenous TRPV1 agonist.[74] Anandamide has also been found to activate TRPV1 on sensory neuron terminals, and subsequently cause vasodilation.[29] TRPV1 may also be activated by methanandamide and arachidonyl-2'-chloroethylamide (ACEA).[17]

Sleep

Increased endocannabinoid signaling within the

nocturnal.[78]

Physical exercise

The endocannabinoid system is also involved in mediating some of the physiological and cognitive effects of voluntary

euphoriant neurochemicals, contributes to the development of exercise-induced euphoria in humans, a state colloquially referred to as a runner's high.[79][80]

Cannabinoids in plants

The endocannabinoid system is by

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.[82] The endocannabinoid Docosatetraenoylethanolamide has been found in Tropaeolum tuberosum (Mashua) and Leonotis leonurus (Lion's tail)[83] Maca contains several N-benzylamides referred to as "macamides" that are structurally related to endocannabinoids such as the N-Benzyl analog of Oleamide.[84] Echinacea contains alkylamides structurally related to endocannabinoids.[85]

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

See also

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