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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endogenous cannabinoid system is an ubiquitous lipid signalling system that appeared early in evolution and which has important regulatory functions throughout the body in all vertebrates. The main endocannabinoids (endogenous cannabis-like substances) are small molecules derived from arachidonic acid, anandamide (arachidonoylethanolamide) and 2-arachidonoylglycerol. They bind to a family of G-protein-coupled receptors, of which the cannabinoid CB(1) receptor is densely distributed in areas of the brain related to motor control, cognition, emotional responses, motivated behaviour and homeostasis. Outside the brain, the endocannabinoid system is one of the crucial modulators of the autonomic nervous system, the immune system and microcirculation. Endocannabinoids are released upon demand from lipid precursors in a receptor-dependent manner and serve as retrograde signalling messengers in GABAergic and glutamatergic synapses, as well as modulators of postsynaptic transmission, interacting with other neurotransmitters, including dopamine. Endocannabinoids are transported into cells by a specific uptake system and degraded by two well-characterized enzymes, the fatty acid amide hydrolase and the monoacylglycerol lipase. Recent pharmacological advances have led to the synthesis of cannabinoid receptor agonists and antagonists, anandamide uptake blockers and potent, selective inhibitors of endocannabinoid degradation. These new tools have enabled the study of the physiological roles played by the endocannabinoids and have opened up new strategies in the treatment of pain, obesity, neurological diseases including multiple sclerosis, emotional disturbances such as anxiety and other psychiatric disorders including drug addiction. Recent advances have specifically linked the endogenous cannabinoid system to alcoholism, and cannabinoid receptor antagonism now emerges as a promising therapeutic alternative for alcohol dependence and relapse.
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PMID:The endocannabinoid system: physiology and pharmacology. 1555 Apr 44

The endogenous levels of the two cannabinoid receptor ligands 2-arachidonoyl glycerol and anandamide, and their respective congeners, monoacyl glycerols and N-acylethanolamines, as well as the phospholipid precursors of N-acylethanolamines, were measured by gas chromatography-mass spectrometry in glioblastoma (WHO grade IV) tissue and meningioma (WHO grade I) tissue and compared with human non-tumour brain tissue. Furthermore, the metabolic turnover of N-acylethanolamines was compared by measurements of the enzymatic activity of N-acyltransferase, N-acylphosphatidylethanolamine-hydrolysing phospholipase D and fatty acid amide hydrolase in the same three types of tissue. Glioblastomas were characterized by enhanced levels of N-acylethanolamines (eightfold, 128 +/- 59 pmol/micromol lipid phosphorus) including anandamide (17-fold, 4.6 +/- 3.1 pmol/micromol lipid phosphorus) and several species of N-acylphosphatidylethanolamines (three to eightfold). This was accompanied by a more than 60% reduction in the enzyme activities of N-acylphosphatidylethanolamine-hydrolysing phospholipase D and fatty acid amide hydrolase. By contrast, meningiomas were characterized by a massively enhanced level of 2-monoacyl glycerols (20-fold, 2293 +/- 361 pmol/micromol lipid phosphorus) including 2-arachidonoyl glycerol (20-fold, 1524 +/- 361 pmol/micromol lipid phosphorus). This was accompanied by an enhanced in vitro conversion of phosphatidylcholine to monoacyl glycerol (fivefold). The enhanced level of the 2-arachidonoyl glycerol, anandamide and other N-acylethanolamines detected in the two types of tumour tissue may possibly act as endogenous anti-tumour mediators by stimulation of both cannabinoid and non-cannabinoid receptor-mediated mechanisms.
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PMID:Endocannabinoid metabolism in human glioblastomas and meningiomas compared to human non-tumour brain tissue. 1581 53

A cannabinoid receptor orthologue (CiCBR) has been described in the sea squirt Ciona intestinalis. Here we report that CiCBR mRNA expression is highest in cerebral ganglion, branchial pharynx, heart and testis of C. intestinalis, and that this organism also contains cannabinoid receptor ligands and some of the enzymes for ligand biosynthesis and inactivation. Using liquid chromatography-mass spectrometry, the endocannabinoid anandamide was found in all tissues analysed (0.063-5.423 pmol/mg of lipid extract), with the highest concentrations being found in brain and heart. The endocannabinoid 2-arachidonoylglycerol (2-AG) was fivefold more abundant than anandamide, and was most abundant in stomach and intestine and least abundant in heart and ovaries (2.677-50.607 pmol/mg of lipid extract). Using phylogenomic analysis, we identified orthologues of several endocannabinoid synthesizing and degrading enzymes. In particular, we identified and partly sequenced a fatty acid amide hydrolase (FAAH) orthologue, showing 44% identity with human FAAH and containing nearly all the amino acids necessary for a functional FAAH enzyme. Ciona intestinalis also contained specific binding sites for cannabinoid receptor ligands, and an amidase enzyme with pH-dependency and subcellular/tissue distribution similar to mammalian FAAHs. Finally, a typical C. intestinalis behavioural response, siphon reopening after closure induced by mechanical stimulation, was inhibited by the cannabinoid receptor agonist HU-210, and this effect was significantly attenuated by mammalian cannabinoid receptor antagonists.
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PMID:Occurrence and possible biological role of the endocannabinoid system in the sea squirt Ciona intestinalis. 1593 35

Anandamide (N-arachidonylethanolamine) is an endogenous cannabinoid receptor ligand that has been implicated in various physiological and pathophysiological functions. In the present study, a liquid-liquid extraction-based reversed-phase HPLC method with fluorometric detection was validated and applied for the analysis of anandamide in human plasma. Following derivatization with the fluorogenic reagent 4-(N,N-dimethylaminosulfonyl)-7-(N-chloroformylmethyl-N-methyl-amino)-2,1,3-benzoxadiazole (DBD-COCl), the analyte was separated using an acetonitrile-water gradient at a flow rate of 0.8 mL/min, and spectrophotometric detection at 560 nm with an excitation wavelength of 450 nm. The retention times for anandamide and R+-methanandamide (internal standard) were 27.1 and 30.7 min, respectively. The validated quantification range was 1-15 ng/mL. The developed procedure was applied to determine anandamide levels in human plasma following a 24 h incubation of human whole blood at 37 degrees C in the presence or absence of phenylmethylsulfonyl fluoride, an inhibitor of the anandamide-degrading enzyme fatty acid amide hydrolase. Anandamide levels determined under both conditions were within the validated concentration range with anandamide levels being 2.3-fold higher in plasma from PMSF-treated blood.
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PMID:Determination of the endocannabinoid anandamide in human plasma by high-performance liquid chromatography. 1618 13

There is recent behavioral evidence that fatty acid amide hydrolase (FAAH) inhibitors produce a subset of cannabinoid receptor agonist effects, suggesting both anandamide-specific behavioral functions and possible regional differences in FAAH inhibitory effects. Here, we introduce a novel imaging method to quantify regional differences in brain FAAH activity. Upon intravenous [3H]anandamide administration, brain FAAH activity generates [3H]arachidonic acid, which is promptly trapped in membrane phospholipids. As a result, wild-type (WT) brains accumulate tritium in a regionally specific manner that is dependent upon regional FAAH activity, whereas brains from FAAH knockout (KO) mice show a uniform [3H]anandamide distribution. Increasing doses of anandamide + [3H]anandamide fail to alter regional tritium accumulation, suggesting insensitivity toward this process by anandamide-induced changes in regional cerebral blood flow. Regional tritiated metabolite levels in WT brains were highest in the somatosensory and visual cortices and the thalamus. Treatment with methylarachidonyl fluorophosphonate (MAFP) (1 mg/kg i.p.) reduced regional tritium accumulation in the somatosensory and visual cortices (p < 0.01), and at higher doses, the thalamus (p < 0.05). The selective FAAH inhibitor 1-oxazolo[4,5-b]pyridin-2-yl-1-dodecanone (CAY10435), although having similar efficacy as MAFP in reducing tritium in the thalamus and somatosensory and visual cortices, also reduces caudate putamen and cerebellum (p < 0.01) activity. These data indicate FAAH activity generates heterogeneous regional accumulation of [3H]anandamide and metabolites, and they suggest the modulation of endocannabinoid tone by FAAH inhibitors depends upon not only the dose and compound used but also on the degree of FAAH expression in the brain regions examined. This imaging method determines regionally specific FAAH inhibition and can elucidate the in vivo effects of pharmacological agents targeting anandamide inactivation.
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PMID:Ex vivo imaging of fatty acid amide hydrolase activity and its inhibition in the mouse brain. 1627 11

Despite their different chemical structures, delta9-tetrahydrocannabinol (THC) and anandamide (AEA) have common pharmacological properties. This study was aimed at finding new cannabinoid receptor ligands that overcome the instability of AEA and its analogues. To this end we planned the synthesis of a series of compounds which retained both a rigid structure, like that of plant cannabinoids, and a flexible portion similar to that of anandamide. Binding studies on CB1 and CB2 receptors, anandamide membrane transporter (AMT), and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds have high affinity and specificity for cannabinoid CB1 and CB2 receptors. Compound 25 is a potent CB1 and CB2 ligand, with affinity constants significantly lower than AEA and similar to WIN 55-212, compound 52 is a potent CB2 ligand, although not very selective over CB1 receptors, and compound 43 is CB2 ligand, with at least a 26-fold selectivity over CB1 receptors. Compound 25 behaved as a inverse agonist at CB1 receptors as assessed in the cyclic AMP functional assay.
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PMID:Design, synthesis, and binding studies of new potent ligands of cannabinoid receptors. 1627 94

In the ventrolateral periaqueductal gray (PAG), activation of excitatory output neurons projecting monosynaptically to OFF cells in the rostral ventromedial medulla (RVM) causes antinociceptive responses and is under the control of cannabinoid receptor type-1 (CB1) and vanilloid transient receptor potential vanilloid type 1 (TRPV1) receptors. We studied in healthy rats the effect of elevation of PAG endocannabinoid [anandamide and 2-arachidonoylglycerol (2-AG)] levels produced by intra-PAG injections of the inhibitor of fatty acid amide hydrolase URB597 [cyclohexylcarbamic acid-3'-carbamoyl-biphenyl-3-yl ester] on 1) nociception in the "plantar test" and 2) spontaneous and tail-flick-related activities of RVM neurons. Depending on the dose or time elapsed since administration, URB597 (0.5-2.5 nmol/rat) either suppressed or increased thermal nociception via TRPV1 or CB1 receptors, respectively. TRPV1 or cannabinoid receptor agonists capsaicin (6 nmol) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3,-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate [WIN55,212-2 (4 nmol)] also suppressed or enhanced nociception, respectively. URB597 dose dependently enhanced PAG anandamide and 2-AG levels, with probable subsequent activation of TRPV1/CB1 receptors and only CB1 receptors, respectively. The TRPV1-mediated antinociception and CB1-mediated nociception caused by URB597 correlated with enhanced or reduced activity of RVM OFF cells, suggesting that these effects occur via stimulation or inhibition of excitatory PAG output neurons, respectively. Accordingly, several ventrolateral PAG neurons were found by immunohistochemistry to coexpress TRPV1 and CB1 receptors. Finally, at the highest doses tested, URB597 (4 nmol/rat) and, as previously reported, WIN55,212-2 (25-100 nmol) also caused CB(1)-mediated analgesia, correlating with stimulation (possibly disinhibition) of RVM OFF cells. Thus, endocannabinoids affect the descending pathways of pain control by acting at either CB1 or TRPV1 receptors in healthy rats.
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PMID:Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors. 1628 79

The demonstration of the essential role of fatty acid amide hydrolase (FAAH) in hydrolyzing endogenous bioactive fatty acid derivatives has launched the quest for the discovery of inhibitors for this enzyme. Along this line, a set of 58 imidazolidine-2,4-dione and 2-thioxoimidazolidin-4-one derivatives was evaluated as FAAH inhibitors. Among these compounds, 3-substituted 5,5'-diphenylimidazolidine-2,4-dione and 3-substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one derivatives were previously described as CB(1) cannabinoid receptor ligands. In the present study, we synthesized several derivatives exhibiting interesting FAAH inhibitory activity and devoid of affinity for the CB(1) and CB(2) cannabinoid receptors. For instance, 3-heptyl-5,5'-diphenylimidazolidine-2,4-dione (14) and 5,5'-diphenyl-3-tetradecyl-2-thioxo-imidazolidin-4-one (46) showed pI(50) values of 5.12 and 5.94, respectively. In conclusion, it appears that even though several 3-substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one and 3-substituted 5,5'-diphenylimidazolidine-2,4-dione derivatives have been previously shown to behave as CB(1) cannabinoid receptor ligands, appropriate substitutions of these templates can result in FAAH inhibitors devoid of affinity for the cannabinoid receptors.
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PMID:Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates. 1639 27

The endocannabinoid anandamide (AEA) has many neurovascular activities. However, it is not yet clear how AEA can be metabolized at the neurovascular interface, and how it can move through the vascular and the cerebral compartments. The results reported in this article show that isolated bovine brain microvessels, an ex vivo model of the blood-brain barrier, have detectable levels of endogenous AEA and possess the biochemical machinery to bind and metabolize it, i.e. type-1 and type-2 cannabinoid receptors (CB1R and CB2R), a selective AEA membrane transporter (AMT), an AEA-degrading fatty acid amide hydrolase, and the AEA-synthesizing enzymes N-acyltransferase and N-acyl-phosphatidylethanolamines-specific phospholipase D. We also show that activation of CB1R enhances AMT activity through increased nitric oxide synthase (NOS) activity and subsequent increase of NO production. AMT activity is instead reduced by activation of CB2R, which inhibits NOS and NO release. In addition, binding experiments and immunoelectronmicroscopy demonstrate that different endothelial cells vary in the expression of CB1R and CB2R on the luminal and/or abluminal sides. The different localization of CBRs can lead to a diverse effect on AMT activity on the luminal and abluminal membranes, suggesting that the distribution of these receptors may drive AEA directional transport through the blood-brain barrier and other endothelial cells.
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PMID:Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells. 1654 70

Extracts of Cannabis sativa have been used for their calming and sedative effects for centuries. Recent developments in drug discovery have suggested that modulation of neuronal endogenous cannabinoid signaling systems could represent a novel approach to the treatment of anxiety-related disorders while minimizing the adverse effects of direct acting cannabinoid receptor agonists. In this study, we evaluated the effects of direct cannabinoid receptor agonists and antagonists and endocannabinoid-modulating drugs on anxiety-like behavior in mice using the elevated-plus maze. We found that the direct CB1 receptor agonists (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP 55,940) (0.001-0.3 mg/kg) and 2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate) (WIN 55212-2) (0.3-10 mg/kg) increased time spent on the open arms (To) at low doses only. At the highest doses tested, both compounds altered overall locomotor activity. In contrast, Delta9-tetrahydrocannabinol (0.25-10 mg/kg) produced a dose-dependent reduction in To. The endocannabinoid uptake/catabolism inhibitor 4-hydroxyphenylarachidonylamide (AM404) (0.3-10 mg/kg) produced an increase in To at low doses and had no effect at the highest dose tested. The fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597) (0.03-0.3 mg/kg) produced a monophasic, dose-dependent increase in To. The CB1 receptor antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716) (1-10 mg/kg) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (1-10 mg/kg) produced dose-related decreases in To. These data indicate that activation of CB1 cannabinoid receptors reduces anxiety-like behaviors in mice and further support an anxiolytic role for endogenous cannabinoid signaling. These results suggest that pharmacological modulation of this system could represent a new approach to the treatment of anxiety-related psychiatric disorders.
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PMID:Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. 1656 53


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