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Theendocannabinoid system (ECS) is a biological system composed ofendocannabinoids, which areneurotransmitters that bind tocannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout thecentral nervous system (including thebrain) andperipheral nervous system.[1][2] It is found in animals as simple ashydras, but absent ininsects, who are hypothesized to have lost it due to a lack ofarachidonic acid.[3] The endocannabinoid system is still not fully understood, but may be involved in regulating physiological andcognitive processes, includingfertility,[4]pregnancy,[5]pre- andpostnatal development,[6][7][8] various activity of immune system,[9]appetite,pain-sensation,mood, andmemory, and in mediating thepharmacological effects ofcannabis.[10][11] The ECS plays an important role in multiple aspects ofneural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.[12]
Two primary cannabinoid receptors have been identified:CB1, first cloned (or isolated) in 1990; andCB2, 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 neurotransmitteranandamide, 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.[13]
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.[14][15][16][17]
The endocannabinoid system, broadly speaking, includes:
Theneurons,neural pathways, 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 thatcannabinoids act asneuromodulators,[19][20][21] or regulators of many neurons and neural signals, for a variety of processes, includingmotor learning,[22]appetite,[23] andpain sensation,[24] among other cognitive and physical processes. The CB1 receptor in the endocannabinoid system shows significant overlap with theorexinergic projection system, a network of hypothalamic projections that regulate many of the same physical and cognitive functions.[25] Moreover, CB1 iscolocalized on orexin projection neurons in thelateral hypothalamus and many output structures of the orexin system,[25][26] where the CB1 andorexin receptor 1 (OX1) receptors physically and functionally join to form the CB1–OX1receptor heterodimer.[25][27][28]
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.[29] 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 thebasal ganglia andcerebellum, regions of the brain involved in the initiation and coordination of movement.[30] 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 receptorknockout mice found cannabinoid responsiveness even when these receptors were not being expressed, indicating that an additional binding receptor may be present in the brain.[30] Binding has been demonstrated by2-arachidonoylglycerol (2-AG) on theTRPV1 receptor suggesting that this receptor may be a candidate for the established response.[31]
In addition to CB1 and CB2, certainorphan receptors are known to bind endocannabinoids as well, includingGPR18,GPR55 (a regulator ofneuroimmune function), andGPR119. CB1 has also been noted to form a functional humanreceptor heterodimer in orexin neurons withOX1, the CB1–OX1 receptor, which mediates feeding behavior and certain physical processes such as cannabinoid-inducedpressor responses which are known to occur through signaling in therostral ventrolateral medulla.[32][33]
During neurotransmission, the pre-synaptic neuron releases neurotransmitters into thesynaptic 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 ofsecond messenger cascades. Based on the cell, these effects may result in the on-site synthesis of endogenous cannabinoidsanandamide or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium.[29] 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 thestria terminalis, calcium entry through voltage-sensitive calcium channels produced an L-type current resulting in 2-AG production, while activation ofmGluR1/5 receptors triggered the synthesis of anandamide.[31]
Evidence suggests that the depolarization-induced influx of calcium into the post-synaptic neuron causes the activation of an enzyme calledtransacylase. This enzyme is suggested to catalyze the first step of endocannabinoid biosynthesis by convertingphosphatidylethanolamine, a membrane-resident phospholipid, intoN-acyl-phosphatidylethanolamine (NAPE). Experiments have shown thatphospholipase D cleaves NAPE to yield anandamide.[34][35] This process is mediated bybile acids.[36][37]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.[38] 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 toglial cell inactivation. Endocannabinoids are taken up by a transporter on the glial cell and degraded byfatty acid amide hydrolase (FAAH), which cleaves anandamide intoarachidonic acid andethanolamine ormonoacylglycerol lipase (MAGL), and 2-AG into arachidonic acid and glycerol.[39] While arachidonic acid is a substrate forleukotriene andprostaglandin synthesis, it is unclear whether this degradative byproduct has unique functions in thecentral nervous system.[40][41] 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.[30] 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.[42]
Cannabinoid receptors are G-protein coupled receptors located on the pre-synaptic membrane. While there have been some papers that have linked concurrent stimulation ofdopamine and CB1 receptors to an acute rise incyclic adenosine monophosphate (cAMP) production, it is generally accepted that CB1 activation via cannabinoids causes a decrease in cAMP concentration[43] by inhibition ofadenylyl cyclase and a rise in the concentration ofmitogen-activated protein kinase (MAP kinase).[18][30] 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 thePI3/PKB andMEK/ERK pathway.[44][45] Results from rat hippocampalgene chip data after acute administration oftetrahydrocannabinol (THC) showed an increase in the expression of transcripts encodingmyelin basic protein, endoplasmic proteins,cytochrome oxidase, and two cell adhesion molecules:NCAM, and SC1; decreases in expression were seen in bothcalmodulin andribosomal RNAs.[46] In addition, CB1 activation has been demonstrated to increase the activity of transcription factors likec-Fos andKrox-24.[45]
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The molecular mechanisms of the endocannabinoid system are primarily concerned with certainvoltage-gated andligand-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-dependentN-,P/Q- andL-typecalcium channels.[47][48] This reduction in activity means that depolarization of affected cells is less likely to occur, and thus neural signalling is reduced.[47][48] In addition to acting on calcium channels, activation ofGi/o andGs, the two most commonly coupled G-proteins to cannabinoid receptors, has been shown to modulatepotassium channel activity. Recent studies have found that CB1 activation specifically facilitates potassium ion flux throughGIRKs, a family ofpotassium channels.[48] Immunohistochemistry experiments demonstrated that CB1 is co-localized with GIRK andKv1.4 potassium channels, suggesting that these two may interact in physiological contexts.[49]
In thecentral nervous system, CB1 receptors influence neuronal excitability, reducing the incoming synaptic input.[50]This mechanism, known aspresynaptic 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 ofadenylyl cyclase andprotein kinase A.[51]Direct effects of CB1 receptors on membrane excitability have been reported, and strongly impact the firing of cortical neurons.[52]A series of behavioral experiments demonstrated thatNMDAR, an ionotropicglutamate receptor, and themetabotropic glutamate receptors (mGluRs) work in concert with CB1 to induceanalgesia in mice, although the mechanism underlying this effect is unclear.[citation needed]
Mice treated with THC show suppression oflong-term potentiation in the hippocampus, a process that is essential for the formation and storage of long-term memory.[53] These results may concur with anecdotal evidence suggesting that smoking cannabis impairs short-term memory.[54] 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 cannabinoidHU-210 over several weeks resulted in stimulation of neural growth in the rats'hippocampus region, a part of thelimbic system playing a part in the formation ofdeclarative andspatial memories, but did not investigate the effects on short-term or long-term memory.[55] Taken together, these findings suggest that the effects of endocannabinoids on the various brain networks involved in learning and memory may vary.
In the adult brain, the endocannabinoid system facilitates theneurogenesis of hippocampalgranule cells.[55][56] In thesubgranular zone of thedentate gyrus, multipotent neural progenitors (NP) give rise todaughter cells that, over the course of several weeks, mature into granule cells whose axons project to and synapse onto dendrites on theCA3 region.[57] NPs in the hippocampus have been shown to possess fatty acid amide hydrolase (FAAH) and express CB1 and utilize 2-AG.[56] 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.[55][56]
Endocannabinoids are known to influencesynaptic plasticity, and are in particular thought to mediatelong-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 thestriatum,[58] 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.[59] Typically, these retrograde transmitters are released by the postsynaptic neuron and induce synaptic depression by activating the presynaptic CB1 receptors.[59]
It has further been suggested that different endocannabinoids, i.e., 2-AG and anandamide, might mediate different forms of synaptic depression through different mechanisms.[31] The study conducted with thebed 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 channels, while anandamide was synthesized aftermGluR5 activation and triggeredautocrine signalling onto postsynapticTRPV1 receptors that induced LTD.[31] 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.[60] It is thought that hypothalamic neurons tonically produce endocannabinoids that work to tightly regulatehunger. The amount of endocannabinoids produced is inversely correlated with the amount ofleptin in the blood.[61] For example, mice without leptin not only become massively obese but express abnormally high levels of hypothalamic endocannabinoids as a compensatory mechanism.[23] Similarly, when these mice were treated with an endocannabinoid inverse agonists, such asrimonabant, food intake was reduced.[23] When the CB1 receptor isknocked 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 thenucleus accumbens and increased pleasure-related behavior after administration of a sucrose solution.[62] A related study found that endocannabinoids affect taste perception in taste cells.[63] 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.[60]
The endocannabinoid system has been shown to have ahomeostatic role by controlling several metabolic functions, such as energy storage and nutrient transport. It acts on peripheral tissues such asadipocytes,hepatocytes, thegastrointestinal tract, theskeletal muscles and the endocrinepancreas. It has also been implied in modulatinginsulin sensitivity. Through all of this, the endocannabinoid system may play a role in clinical conditions, such asobesity,diabetes, andatherosclerosis, which may also give it acardiovascular role.[64]
While the secretion ofglucocorticoids 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 thehypothalamic-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 ofcorticosterone; 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 antagonistAM251, supporting the conclusion that these effects were cannabinoid-receptor dependent.[65] 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 regulatinganxiety-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.[66]
In laboratory experiments, activation of cannabinoid receptors had an effect on the activation ofGTPases inmacrophages,neutrophils, andbone marrow cells. These receptors have also been implicated in the migration ofB cells into themarginal zone and the regulation ofIgM levels.[67]
The developingembryo expresses cannabinoid receptors early in development that are responsive toanandamide secreted in theuterus. 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.[68] 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.[69][70]
Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in theautonomic 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 fromsympathetic 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.[30]
At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in thedorsal horn, possibly by modulating descendingnoradrenaline input from thebrainstem.[30] As many of these fibers are primarilyGABAergic, cannabinoid stimulation in the spinal column results in disinhibition that should increase noradrenaline release and attenuation of noxious-stimuli-processing in the periphery anddorsal root ganglion.
The endocannabinoid most researched in pain ispalmitoylethanolamide. 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 thePPAR-alpha receptor, theTRPV receptor and the GPR55 receptor. Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications[71] 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 onemechanism[72] for analgesia by acetaminophen (paracetamol).
Endocannabinoids are involved inplacebo induced analgesia responses.[73]
Anandamide andN-arachidonoyl dopamine (NADA) have been shown to act on temperature-sensingTRPV1 channels, which are involved in thermoregulation.[74] TRPV1 is activated by the exogenous ligandcapsaicin, the active component of chili peppers, which is structurally similar to endocannabinoids. NADA activates the TRPV1 channel withanEC50 of approximately of 50 nM.[clarify] The high potency makes it the putative endogenous TRPV1 agonist.[75] Anandamide has also been found to activate TRPV1 on sensory neuron terminals, and subsequently causevasodilation.[30] TRPV1 may also be activated bymethanandamide andarachidonyl-2'-chloroethylamide (ACEA).[18]
Increased endocannabinoid signaling within thecentral nervous system promotes sleep-inducing effects.Intercerebroventricular administration of anandamide in rats has been shown to decrease wakefulness and increaseslow-wave sleep andREM sleep.[76] Administration of anandamide into thebasal forebrain of rats has also been shown to increase levels ofadenosine, which plays a role in promoting sleep and suppressing arousal.[77] REM sleep deprivation in rats has been demonstrated to increase CB1 receptor expression in the central nervous system.[78] Furthermore, anandamide levels possess acircadian 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 arenocturnal.[79]
The endocannabinoid system is also involved in mediating some of the physiological and cognitive effects of voluntaryphysical exercise in humans and other animals, such as contributing to exercise-inducedeuphoria as well as modulatinglocomotor activity andmotivational salience forrewards.[80][81] In humans, theplasma concentration of certain endocannabinoids (i.e.,anandamide) have been found to rise during physical activity;[80][81] since endocannabinoids can effectively penetrate theblood–brain barrier, it has been suggested that anandamide, along with othereuphoriant neurochemicals, contributes to the development of exercise-induced euphoria in humans, a state colloquially referred to as arunner's high.[80][81]
The endocannabinoid system is bymolecularphylogenetic distribution of apparently ancient lipids in theplant kingdom, indicative ofbiosyntheticplasticity and potentialphysiological roles of endocannabinoid-like lipids in plants,[82] and detection ofarachidonic acid (AA) indicateschemotaxonomic connections betweenmonophyletic 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 aschemical plant-pollinator interactions,communication anddefense mechanisms. The two novel EC-like molecules derived from theeicosatetraenoic acidjuniperonic acid, anomega-3 structuralisomer of AA, namely juniperoyl ethanolamide and 2-juniperoyl glycerol (1/2-AG) ingymnosperms,lycophytes and fewmonilophytes, show AA is anevolutionarily conservedsignalling molecule that acts in plants in response tostress similar to that inanimal systems.[83] The endocannabinoidDocosatetraenoylethanolamide has been found inTropaeolum tuberosum (mashua) andLeonotis leonurus (lion's tail).[84] Maca contains several N-benzylamides referred to as "macamides" that are structurally related to endocannabinoids such as the N-Benzyl analog ofoleamide.[85]Echinacea contains alkylamides structurally related to endocannabinoids.[86]
Serinolamide A is a cannabinoid structurally related to endocannabinoids found incyanobacteria such asLyngbya majuscula and other species in theOscillatoria family.
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.
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). CB1knockout 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).
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.
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.
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
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