noladin-ether has been researched along with glyceryl-2-arachidonate* in 18 studies
1 review(s) available for noladin-ether and glyceryl-2-arachidonate
Article | Year |
---|---|
The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications.
Topics: Amides; Amidohydrolases; Amines; Animals; Arachidonic Acids; Binding Sites; Cannabinoid Receptor Modulators; Drug Design; Endocannabinoids; Esters; Ethers; Glycerides; Humans; Ligands; Monoacylglycerol Lipases; Polyunsaturated Alkamides; Receptors, Cannabinoid | 2005 |
17 other study(ies) available for noladin-ether and glyceryl-2-arachidonate
Article | Year |
---|---|
The endocannabinoid 2-AG controls skeletal muscle cell differentiation via CB1 receptor-dependent inhibition of Kv7 channels.
Little is known of the involvement of endocannabinoids and cannabinoid receptors in skeletal muscle cell differentiation. We report that, due to changes in the expression of genes involved in its metabolism, the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) are decreased both during myotube formation in vitro from murine C2C12 myoblasts and during mouse muscle growth in vivo. The endocannabinoid, as well as the CB1 agonist arachidonoyl-2-chloroethylamide, prevent myotube formation in a manner antagonized by CB1 knockdown and by CB1 antagonists, which, per se, instead stimulate differentiation. Importantly, 2-AG also inhibits differentiation of primary human satellite cells. Muscle fascicles from CB1 knockout embryos contain more muscle fibers, and postnatal mice show muscle fibers of an increased diameter relative to wild-type littermates. Inhibition of Kv7.4 channel activity, which plays a permissive role in myogenesis and depends on phosphatidylinositol 4,5-bisphosphate (PIP2), underlies the effects of 2-AG. We find that CB1 stimulation reduces both total and Kv7.4-bound PIP2 levels in C2C12 cells and inhibits Kv7.4 currents in transfected CHO cells. We suggest that 2-AG is an endogenous repressor of myoblast differentiation via CB1-mediated inhibition of Kv7.4 channels. Topics: Animals; Arachidonic Acids; Cell Differentiation; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Endocannabinoids; Gene Silencing; Glycerides; Humans; Inositol Phosphates; KCNQ Potassium Channels; Mice; Muscle Development; Muscle Fibers, Skeletal; Muscle, Skeletal; Myoblasts, Skeletal; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Signal Transduction; Silicone Elastomers; Transfection | 2014 |
Stimulatory and inhibitory roles of brain 2-arachidonoylglycerol in bombesin-induced central activation of adrenomedullary outflow in rats.
2-Arachidonoylglycerol (2-AG) is recognized as a potent endocannabinoid, which reduces synaptic transmission through cannabinoid CB(1) receptors, and is hydrolyzed by monoacylglycerol lipase (MGL) to arachidonic acid (AA), a cyclooxygenase substrate. We already reported that centrally administered MGL and cyclooxygenase inhibitors each reduced the intracerebroventricularly (i.c.v.) administered bombesin-induced secretion of adrenal catecholamines, while a centrally administered CB(1)-antagonist potentiated the response, indirectly suggesting bidirectional roles of brain 2-AG (stimulatory and inhibitory roles) in the bombesin-induced response. In the present study, we separately examined these bidirectional roles using 2-AG and 2-AG ether (2-AG-E) (stable 2-AG analog for MGL) in rats. 2-AG (0.5 μmol/animal, i.c.v.), but not 2-AG-E (0.5 μmol/animal, i.c.v.), elevated basal plasma catecholamines with JZL184 (MGL inhibitor)- and indomethacin (cyclooxygenase inhibitor)-sensitive brain mechanisms. 2-AG-E (0.1 μmol/animal, i.c.v.) effectively reduced the bombesin (1 nmol/animal, i.c.v.)-induced elevation of plasma catecholamines with rimonabant (CB(1) antagonist)-sensitive brain mechanisms. Immunohistochemical studies demonstrated the bombesin-induced activation of diacylglycerol lipase α (2-AG-producing enzyme)-positive spinally projecting neurons in the hypothalamic paraventricular nucleus, a control center of central adrenomedullary outflow. These results directly indicate bidirectional roles of brain 2-AG, a stimulatory role as an AA precursor and an inhibitory role as an endocannabinoid, in the bombesin-induced central adrenomedullary outflow in rats. Topics: Adrenal Medulla; Animals; Arachidonic Acids; Benzodioxoles; Bombesin; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Catecholamines; Cyclooxygenase Inhibitors; Drug Interactions; Endocannabinoids; Glycerides; Indomethacin; Injections, Intraventricular; Lipoprotein Lipase; Male; Monoacylglycerol Lipases; Neurotransmitter Agents; Paraventricular Hypothalamic Nucleus; Piperidines; Pyrazoles; Rats; Rimonabant | 2013 |
Stimulation of accumbens shell cannabinoid CB(1) receptors by noladin ether, a putative endocannabinoid, modulates food intake and dietary selection in rats.
Stimulation of cannabinoid CB(1) receptors in nucleus accumbens shell has been shown to stimulate feeding and enhance positive 'liking' reactions to intraoral sucrose. This study examined the behavioural effects of noladin ether and 2-arachidonoylglycerol following infusion into accumbens shell, on chow intake and food preference in high-carbohydrate and high-fat preferring rats. Noladin ether, potently and dose-dependently stimulated chow intake as compared with 2-arachidonoylglycerol in free-feeding rats. In the diet preference paradigm, in which rats were given free access to both, high-carbohydrate (HC) and high-fat (HF) diets simultaneously, an intra-accumbens administration of noladin ether as well as 2-arachidonoylglycerol, preferentially enhanced fat consumption over carbohydrate in both HF- and HC-preferring rats. These effects were significantly attenuated by the CB(1) receptor antagonist, AM 251. These results suggesting that, the endocannabinoids through CB(1) receptors, affects appetite for specific dietary components. Both these agents exert a specific action on eating motivation and possibly promoting eating by enhancing the incentive value of food. Altogether these findings reinforce the idea that the endogenous cannabinoid system in the accumbens shell may be important to augment reward-driven feeding via modulation of CB(1) receptor signalling pathways. Topics: Animals; Appetite; Arachidonic Acids; Cannabinoid Receptor Modulators; Diet; Diet, High-Fat; Dietary Carbohydrates; Eating; Endocannabinoids; Food Preferences; Glycerides; Hyperphagia; Male; Nucleus Accumbens; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Sucrose | 2012 |
Development of endocannabinoid-based chemical probes for the study of cannabinoid receptors.
We report the synthesis of new chemical probes (1a,b, 2a-c, 3a-c) based on the structure of the main endocannabinoids for their use in biological systems directly or via click chemistry. As proof of concept, 2-arachidonyl glyceryl ether based biotinylated 3b enables direct visualization of CB(1) receptor in cells. These results represent the starting point for the development of advanced small molecule chemical probes able to generate valuable information about the cannabinoid receptors. Topics: Alkenes; Arachidonic Acids; Benzophenones; Binding, Competitive; Biotin; Cannabinoid Receptor Modulators; Cell Line; Click Chemistry; Endocannabinoids; Glycerides; Humans; Ligands; Molecular Probes; Polyunsaturated Alkamides; Radioligand Assay; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship | 2011 |
Resorcinol-sn-glycerol derivatives: novel 2-arachidonoylglycerol mimetics endowed with high affinity and selectivity for cannabinoid type 1 receptor.
Since the discovery of the endocannabinoid system, evidence has been progressively accumulating to suggest that 2-arachidonoylglycerol (2-AG) rather than anandamide (AEA) is the endogenous ligand for both cannabinoid (CB) receptors. Moreover, other studies have shown that another lipid molecule, 2-arachidonyl-glycerol ether (2-AGE, noladin ether), which acts as a full agonist at cannabinoid receptors, might occur in tissues. Having previously designed a resorcinol-AEA hybrid model, in this paper we have explored the cannabinoid receptor binding properties, the CB1 functional activity, and the stability to plasma esterases of a novel series of compounds characterized by the conversion of the amide head into the glycerol-ester or glycerol-ether head, typical of 2-AG or the "putative" endocannabinoid 2-AGE, respectively. Glyceryl esters 39 and 41 displayed greater potency for CB1 (Ki in the nanomolar range) than for CB2 receptors plus the potential to be exploited as useful hits for the development of novel 2-AG mimetics. Topics: Animals; Arachidonic Acids; Brain; CHO Cells; Cricetinae; Cricetulus; Cytochrome P-450 CYP3A; Endocannabinoids; Esterases; Esters; Ethers; Glycerides; HEK293 Cells; Humans; In Vitro Techniques; Mice; Molecular Mimicry; Monoglycerides; Phenols; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Resorcinols; Stereoisomerism; Structure-Activity Relationship | 2011 |
BDNF regulates neuronal sensitivity to endocannabinoids.
The diacylglycerol lipases (DAGLalpha/beta) synthesize 2-arachidonylglycerol (2-AG), the major endocannabinoid in the developing and adult brain (eCB). This lipid acts on cannabinoid receptors to regulate axonal growth and guidance, activity-dependent synaptic plasticity and adult neurogenesis, and can also protect neurons from excitotoxicity. 2-AG action is generally terminated by monoacylglycerol lipase (MAGL), however we know very little about the mechanisms that regulate neuronal sensitivity to eCBs. In the present study we show that the brain-derived neurotrophic factor (BDNF) can determine neuronal sensitivity to eCBs. In this context, in cultured cerebellar granule neurons (CGNs) BDNF increases the expression of CB1 receptor transcripts and decreases expression of MAGL transcripts. Using phosphorylation of Akt as the readout, we show that BDNF can promote a stable increase in neuronal sensitivity to eCBs. For example, concentrations of 2-AG and noladin either (NE) that normally do not lead to Akt phosphorylation in control neurons do so in neurons pre-treated with BDNF. In addition, Akt phosphorylation in response to a wide range of concentrations of NE was always greater in neurons pre-treated with BDNF. Our data suggests the existence of a positive feedback loop that might sustain neuronal survival in the normal brain. Topics: Animals; Animals, Newborn; Arachidonic Acids; Brain-Derived Neurotrophic Factor; Cannabinoid Receptor Modulators; Cells, Cultured; Cerebellum; Down-Regulation; Endocannabinoids; Glycerides; Monoacylglycerol Lipases; Neurons; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Receptor, Cannabinoid, CB1; Up-Regulation | 2009 |
Synthesis and biological evaluation of several structural analogs of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand.
2-Arachidonoylglycerol (2-AG (1)) is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). There is growing evidence that 2-arachidonoylglycerol plays important physiological and pathophysiological roles in various mammalian tissues and cells, though the details remain to be clarified. In this study, we synthesized several remarkable analogs of 2-arachidonoylglycerol, closely related in chemical structure to 2-arachidonoylglycerol: an analog containing an isomer of arachidonic acid with migrated olefins (2-AGA118 (3)), an analog containing a one-carbon shortened fatty acyl moiety (2-AGA113 (4)), an analog containing an one-carbon elongated fatty acyl moiety (2-AGA114 (5)), a hydroxy group-containing analog (2-AGA105 (6)), a ketone group-containing analog (2-AGA109 (7)), and a methylene-linked analog (2-AGA104 (8)). We evaluated their biological activities as cannabinoid receptor agonists using NG108-15 cells which express the CB1 receptor and HL-60 cells which express the CB2 receptor. Notably, these structural analogs of 2-arachidonoylglycerol exhibited only weak agonistic activities toward either the CB1 receptor or the CB2 receptor, which is in good contrast to 2-arachidonoylglycerol which acted as a full agonist at these cannabinoid receptors. These results clearly indicate that the structure of 2-arachidonoylglycerol is strictly recognized by the cannabinoid receptors (CB1 and CB2) and provide further evidence that the cannabinoid receptors are primarily the intrinsic receptors for 2-arachidonoylglycerol. Topics: Arachidonic Acids; Cannabinoid Receptor Agonists; Cell Line; Endocannabinoids; Glycerides; HL-60 Cells; Humans; Indicators and Reagents; Ligands; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Structure-Activity Relationship | 2007 |
Quantitative profiling of endocannabinoids and related compounds in rat brain using liquid chromatography-tandem electrospray ionization mass spectrometry.
A sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is described for the simultaneous identification and quantification of eight endocannabinoid (EC) or related "entourage" compounds in rat brain tissue. Analytes were extracted and purified from rat brain tissue using an ethyl acetate/hexane solvent extraction, followed by a solid phase extraction (SPE) protocol. Chromatographic separation was achieved using a gradient elution, with a mobile phase of acetonitrile, formic acid, and ammonium acetate, at pH 3.6. A Thermo Hypersil C8 HyPurity Advance column (100x2.1 mm i.d., 3 microm) was used with a flow rate of 0.3 ml/min). Anandamide (AEA), 2-arachidonyl glycerol (2-AG), 2-arachidonylglyceryl ether (noladin ether), O-arachidonyl ethanolamide (virodhamine), 2-linoleoyl glycerol (2-LG), arachidonyl glycine, oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA) were quantified by positive ion tandem electrospray ionization mass spectrometry. Internal standards were deuterated AEA, deuterated 2-AG, and heptadecanoyl ethanolamide (HEA). Linearity was proven over the range of 25 fmol to 250 pmol, with a limit of detection of 25 fmol on column for all analytes except 2-AG, noladin ether, and 2-LG (250 fmol). This corresponded to a limit of quantification in biological tissue of 10 pmol/g for all analytes except 2-AG (100 pmol/g). Intra- and interday precision in biological tissue was routinely approximately 20% or lower, and accuracy was between 65% and 155%. This method was used to quantitatively profile regional differences in nine discrete rat brain regions for AEA, 2-AG, 2-LG, OEA, PEA, noladin ether, virodhamine, and arachidonyl glycine. Topics: Animals; Arachidonic Acids; Brain Chemistry; Cannabinoid Receptor Modulators; Cannabinoids; Chromatography, Liquid; Endocannabinoids; Glycerides; Glycine; Male; Oleic Acids; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry | 2007 |
Endothelium-dependent metabolism by endocannabinoid hydrolases and cyclooxygenases limits vasorelaxation to anandamide and 2-arachidonoylglycerol.
The endocannabinoids, N-arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG) are rapidly degraded by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Whilst these lipid mediators are known to modulate vascular tone, the extent to which they are inactivated via local metabolism in the vasculature remains unclear.. In rat isolated small mesenteric arteries, the regulatory role of FAAH, MGL and cyclooxygenase (COX) in relaxant responses to anandamide and 2-AG was evaluated by using inhibitors of these enzymes. Relaxations to non-hydrolysable analogues of endocannabinoids and arachidonic acid were also examined.. Relaxation to anandamide but not 2-AG was potentiated by the selective FAAH inhibitor, URB597 (1 microM). In contrast, MAFP (10 microM; an inhibitor of FAAH and MGL) enhanced responses to both anandamide and 2-AG. Inhibition of COX-1 by indomethacin (10 microM) potentiated relaxations to 2-AG, whereas inhibition of COX-2 by nimesulide (10 microM) potentiated anandamide-induced relaxation. With the exception of MAFP, effects of FAAH and COX inhibitors were dependent on the endothelium. Relaxation to methanandamide and noladin ether, the non-hydrolysable analogues of anandamide and 2-AG respectively, were insensitive to the enzyme inhibitors.. This study shows that local activity of FAAH, MGL and COX, which is present largely in the endothelium, limits the vasodilator action of endocannabinoids in rat small mesenteric arteries. Despite the differential roles played by these enzymes on relaxation to anandamide versus 2-AG, our results suggest that inhibitors of these enzymes enhance the vascular impact of endocannabinoids. Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Cannabinoid Receptor Modulators; Carbamates; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Endocannabinoids; Endothelium, Vascular; Enzyme Inhibitors; Glycerides; Hydrolases; In Vitro Techniques; Lectins; Lectins, C-Type; Male; Membrane Proteins; Mesenteric Artery, Superior; Organophosphonates; Polyunsaturated Alkamides; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Receptors, Cell Surface; Vasodilation; Vasodilator Agents | 2007 |
Differential effects of endocannabinoids on [(3)H]-GABA uptake in the rat globus pallidus.
In the globus pallidus, cannabinoid CB(1) receptors are localized pre-synaptically on GABAergic neurons. We assessed the influence of the endocannabinoids, anandamide, 2-arachidonoyl-glycerol (2-AG) and noladin ether, on the uptake of [(3)H]-GABA in pallidal slices from rat. Both 2-AG and noladin ether increased [(3)H]-GABA uptake (by 40.8 +/- 8.0% and 38.4 +/- 12.5%). The effect of 2-AG was blocked by the cannabinoid CB(1) receptor antagonist AM 251. In contrast, neither anandamide nor the agonist WIN 55,212-2 had an effect on [(3)H]-GABA uptake. Different roles might be played by different endocannabinoids, both physiologically and in basal ganglia disorders, such as Parkinson's disease. Topics: Animals; Arachidonic Acids; Binding, Competitive; Cannabinoid Receptor Modulators; Endocannabinoids; gamma-Aminobutyric Acid; Globus Pallidus; Glycerides; In Vitro Techniques; Male; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Tritium | 2005 |
The endocannabinoid noladin ether acts as a full agonist at human CB2 cannabinoid receptors.
Noladin ether (NE) is a putative endogenously occurring cannabinoid demonstrating agonist activity at CB1 receptors. Because of reported selective affinity for CB1 receptors, the pharmacological actions of NE at CB2 receptors have not been examined. Therefore, the purpose of this study was to characterize the binding and functional properties of NE at human CB2 receptors stably expressed in Chinese hamster ovary (CHO) cells as well as in HL-60 cells, which express CB2 receptors endogenously. Surprisingly, in transfected CHO cells, NE exhibits a relatively high nanomolar affinity for CB2 receptors (K(i) = 480 nM), comparable to that observed for the endocannabinoid 2-arachidonoyl glycerol (2-AG) (K(i) = 1016 nM). Furthermore, NE activates G proteins and inhibits the intracellular effector adenylyl cyclase with equivalent efficacy relative to the full cannabinoid agonists 2-AG and CP 55,940 (CP) [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol]. The rank order of potency for G protein activation and effector regulation by the three agonists is similar to their apparent affinity for CB2 receptors; CP > NE > or = 2-AG. Regulation of adenylyl cyclase activity by all agonists is inhibited by pertussis toxin pretreatment or by coincubation with AM630 [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)-methanone], a CB2 antagonist. Chronic treatment with NE or CP results in CB2 receptor desensitization and down-regulation. All agonists also inhibit adenylyl cyclase activity in HL-60 cells. Together, these data indicate that NE acts as a full agonist at human CB2 receptors and thus might have important physiological functions at peripheral cannabinoid receptors. Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Analgesics; Animals; Arachidonic Acids; Binding, Competitive; Biotransformation; CHO Cells; Cricetinae; Cyclic AMP; Cyclohexanols; Down-Regulation; Endocannabinoids; Enzyme Inhibitors; Glycerides; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); HL-60 Cells; Humans; In Vitro Techniques; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, G-Protein-Coupled; Transfection | 2005 |
Agonist-directed trafficking of response by endocannabinoids acting at CB2 receptors.
This study examined the ability of the endocannabinoids 2-arachidonoyl glycerol (2-AG) and noladin ether as well as the synthetic cannabinoid CP-55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol] to regulate three intracellular effectors via CB2 receptors in transfected Chinese hamster ovary cells. Although the three agonists regulate all effectors with equivalent efficacy, the rank order of potencies differs depending on which effector is evaluated. Noladin ether and CP-55,940 most potently inhibit adenylyl cyclase, requiring higher concentrations to stimulate the extracellular signal-regulated kinase subgroup of the mitogen-activated protein kinases (extracellular signal-regulated kinase-mitogen-activated protein kinase; ERK-MAPK) and Ca(2+)-transients. In contrast, 2-AG most potently activates ERK-MAPK, necessitating greater concentrations to inhibit adenylyl cyclase and even higher amounts to stimulate Ca(2+)-transients. Endocannabinoids also seem to be more "efficient" agonists at CB2 receptors relative to synthetic agonists. 2-AG and noladin ether require occupancy of less than one-half the number of receptors to produce comparable regulation of adenylyl cyclase and ERK-MAPK, relative to the synthetic cannabinoid CP-55,940. The CB2 antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl)-ethyl]-1H-indol-3-yl](4-methoxyphenyl)-methanone (AM630) reverses the actions of all agonists except Ca(2+)-transient stimulation by 2-AG. However, the effect of 2-AG on Ca(2+)-transients is attenuated by a second CB2 antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-1-pyrazole-3-carboxamide (SR144528). This suggests that 2-AG stimulates Ca(2+)-transients by binding to sites on CB2 receptors distinct from those occupied by AM630 and the other cannabinoids examined. Agonists produce no effects in pertussis toxin-treated cells. In summary, cannabinoid agonists distinctly bind to CB2 receptors and display different rank order of potencies and fractional receptor occupancies for regulation of intracellular effectors. These data provide direct evidence for agonist-directed trafficking of response by endocannabinoids acting at CB2 receptors. Topics: Adenylyl Cyclases; Animals; Arachidonic Acids; Binding, Competitive; Blotting, Western; Calcium Signaling; Cannabinoid Receptor Modulators; Cell Membrane; CHO Cells; Cricetinae; Cyclic AMP; Cyclohexanols; DNA, Complementary; Endocannabinoids; Enzyme-Linked Immunosorbent Assay; Glycerides; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Indoles; Mitogen-Activated Protein Kinases; Receptor, Cannabinoid, CB2; Transfection | 2005 |
Persistent anxiogenic effects of a single or repeated doses of cocaine and methamphetamine: interactions with endogenous cannabinoid receptor ligands.
As persistent behavioural changes, such as increased anxiety-related behaviours, can be predicted based on the phenomenon of psychostimulant-induced neuronal plasticity, the time course (3-, 5- and 10-day time points) of the effects of both a single and repeated (daily for 7 days) i.p. administrations of cocaine (COC) and methamphetamine (MA) on anxiety-related behavioural symptoms in the elevated plus-maze test were examined in mice. Furthermore, based on the reported interactions between brain dopamine versus cannabinoid (CB) receptors and the contribution of CB receptors to the occurrence of persistent anxiety-related behavioural symptoms, the interactions of the agonist CP 55940 (CP) and the endogenous ligands anandamide (arachidonylethanolamide: AEA), 2-arachidonylglycerol (ARA), N-arachidonyldopamine (NADA), noladin ether (NL), and virodhamine (VA) with the COC- or MA-induced anxiety-related behaviours were also studied. In both an acute experiment using a single COC (30 mg/kg) or MA (4 mg/kg) dose and a chronic experiment using repeated COC (15 mg/kg) or MA (2 mg/kg) doses, anxiety-related behavioural symptoms were observed similarly at 3- and 5-day time points, but disappeared at the 10-day time point. Among the CB ligands, the agonists CP, AEA, ARA, NADA, and NL provided strong protective effects against each parameter at 3- and 5-day time points. Therefore, it was concluded that both COC and MA caused persistent anxiety-related behavioural symptoms following both a single and repeated treatments. Since these anxiogenic effects were attenuated by the endogenous CB agonists, the involvement of brain CB receptors was suspected. Topics: Analysis of Variance; Animals; Anxiety; Arachidonic Acids; Behavior, Animal; Cannabinoids; Cocaine; Cyclohexanols; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Endocannabinoids; Glycerides; Injections, Intraperitoneal; Male; Maze Learning; Methamphetamine; Mice; Mice, Inbred ICR; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Time Factors | 2005 |
Depolarization-induced suppression of excitation in murine autaptic hippocampal neurones.
Depolarization-induced suppression of excitation and inhibition (DSE and DSI) appear to be important forms of short-term retrograde neuronal plasticity involving endocannabinoids (eCB) and the activation of presynaptic cannabinoid CB1 receptors. We report here that CB1-dependent DSE can be elicited from autaptic cultures of excitatory mouse hippocampal neurones. DSE in autaptic cultures is both more robust and elicited with a more physiologically relevant stimulus than has been thus far reported for conventional hippocampal cultures. An additional requirement for autaptic DSE is filled internal calcium stores. Pharmacological experiments favour a role for 2-arachidonyl glycerol (2-AG) rather than arachidonyl ethanolamide (AEA) or noladin ether as the relevant endocannabinoid to elicit DSE. In particular, the latter two compounds fail to reversibly inhibit EPSCs, a quality inconsistent with the role of bona fide eCB mediating DSE. Delta9-Tetrahydrocannabinol (delta9-THC) fails to inhibit EPSCs, yet readily occludes both DSE and EPSC inhibition by a synthetic CB1 agonist, WIN 55212-2. With long-term exposure (approximately 18 h), delta9-THC also desensitizes CB1 receptors. Lastly, a functional endocannabinoid transporter is necessary for the expression of DSE. Topics: Animals; Arachidonic Acids; Benzoxazines; Calcium; Cannabinoid Receptor Modulators; Cells, Cultured; Dronabinol; Endocannabinoids; Excitatory Postsynaptic Potentials; Glutamic Acid; Glycerides; Hippocampus; Mice; Mice, Inbred C57BL; Morpholines; Naphthalenes; Neuronal Plasticity; Neurons; Nitric Oxide; Patch-Clamp Techniques; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1 | 2005 |
Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons.
Endocannabinoids may serve as retrograde messengers to inhibit neurotransmitter release during depolarization-induced suppression of inhibition (DSI) or excitation (DSE). We therefore tested whether endocannabinoids inhibit N-type voltage-dependent Ca2+ channels by activating G(i/o)-protein-coupled CB1 cannabinoid receptors (CB1R)--a possible mechanism underlying DSI/DSE. Three putative endocannabinoids [2-arachidonylglycerol (2-AG), 2-arachidonyl glycerol ether (2-AGE), and anandamide (AEA)] and the cannabimimetic aminoalkylindole WIN 55,212-2 (WIN) inhibited whole-cell Ca2+ currents in rat sympathetic neurons previously injected with cDNA encoding a human CB1R. Agonist-mediated Ca2+ current inhibition was blocked by a selective CB1R antagonist [SR141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride] and pertussis toxin (PTX) pretreatment. The rank order of potency was WIN (IC50=2 nM)>2-AGE (350 nM) approximately 2-AG (480 nM)>AEA (approximately 3 microM), with each agonist displaying similar efficacy (approximately 50% maximal inhibition). Increasing CB1R expression level significantly enhanced AEA potency. AEA (10 microM) also inhibited Ca2+ channels in a voltage-independent, CB1R-independent, and PTX-insensitive manner, whereas 2-AG and 2-AGE were devoid of this activity. All three endocannabinoids activated G-protein-coupled inwardly rectifying potassium (GIRK) channels, GIRK1/4, heterologously expressed in sympathetic neurons. These results suggest a mechanism by which endocannibinoids might influence presynaptic function. Topics: Animals; Arachidonic Acids; Benzoxazines; Calcium; Calcium Channel Blockers; Calcium Channels, N-Type; Cannabinoids; Dose-Response Relationship, Drug; Endocannabinoids; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Glycerides; GTP-Binding Proteins; Humans; In Vitro Techniques; Male; Morpholines; Naphthalenes; Neurons; Polyunsaturated Alkamides; Potassium Channels; Potassium Channels, Inwardly Rectifying; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1 | 2004 |
Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species.
2-Eicosa-5',8',11',14'-tetraenylglycerol (2-AG ether, HU310, noladin ether) is a metabolically stable ether-linked analogue of 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid receptor ligand. 2-AG ether has been used as a valuable experimental tool by a number of investigators. Recently, several groups reported that 2-AG ether is present in mammalian brains. We examined in detail whether 2-AG ether actually exists in the brains of various mammalian species. We found that 2-AG ether is not present, at least in an appreciable amount, in the rat brain by gas chromatography-mass spectrometry analysis and fluorometric high performance liquid chromatography analysis. The level of 2-AG ether in the rat brain was below 0.2 pmol/g brain, if at all present. Similar results were obtained for the mouse brain, hamster brain, guinea-pig brain and pig brain. The fact that 2-AG ether was not detected in the brains of various mammalian species is consistent with the fact that an ether bond is formed through enzymatic replacement of the fatty acyl moiety of 1-acyl dihydroxyacetone phosphate by a fatty alcohol, the resultant 1-O-alkyl dihydroxyacetone phosphate being a common intermediate of the biosynthesis of ether-linked lipids in mammalian tissues. It is rather questionable whether 2-AG ether is present in appreciable amounts in the brain and acts as an 'endogenous' cannabinoid receptor ligand. Topics: Animals; Arachidonic Acids; Brain Chemistry; Chromatography, High Pressure Liquid; Cricetinae; Endocannabinoids; Glycerides; Glyceryl Ethers; Guinea Pigs; Male; Mass Spectrometry; Mice; Rats; Swine | 2003 |
Comparison of the enzymatic stability and intraocular pressure effects of 2-arachidonylglycerol and noladin ether, a novel putative endocannabinoid.
The endogenous cannabinoids N-arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) are known to decrease intraocular pressure (IOP). Recently, a novel putative endogenous cannabinoid, noladin ether, was isolated in porcine and rat brains. In the present study, both the degradation of endogenous cannabinoids in ocular tissues and the effect on IOP of 2-AG and noladin ether were compared.. The rates of enzymatic degradation for AEA, 2-AG, and noladin ether were determined in bovine cornea and iris-ciliary body homogenates. 2-AG and noladin ether were dissolved in either hydroxypropyl-beta-cyclodextrin (HP-beta-CD) or propylene glycol and administered unilaterally to the rabbit eye. IOPs were measured in the treated and untreated eyes. The CB1 receptor antagonist AM251 was administered topically 15 minutes before the cannabinoids to investigate whether CB1 receptors mediate the effect on IOP produced by 2-AG and noladin ether.. Noladin ether degraded more slowly than either 2-AG or AEA in the iris-ciliary body and cornea homogenates. The effect on IOP of 2-AG was biphasic (i.e., an initial increase in IOP followed by a reduction in the treated eye). Noladin ether decreased IOP immediately after topical administration, and no initial IOP increase was observed in the treated eye. The CB1 receptor antagonist AM251 (25 micro g) blocked the effect on IOP of noladin ether but did not affect the action of 2-AG.. Topical administration of the novel putative endogenous cannabinoid noladin ether decreased IOP in rabbits. This IOP reduction was most probably mediated through the CB1 receptor. The effect on IOP of noladin ether differed from those of the known endogenous cannabinoids AEA and 2-AG, probably because of its more stable chemical structure. Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cattle; Ciliary Body; Cornea; Endocannabinoids; Enzyme Stability; Female; Glycerides; Intraocular Pressure; Iris; Male; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rabbits; Receptors, Cannabinoid; Receptors, Drug | 2002 |