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

We have recently described the dose-response effect of anandamide (AEA), the N-amide derivative of arachidonic acid that acts as an endogenous ligand for the cannabinoid receptor, on extrapyramidal function. The present study has been designed to examine the time-course of this effect. To this end, adult male rats were submitted to an acute i.p. injection of AEA, delta9-tetrahydrocannabinol (THC) or vehicle and examined at different times after drug administration. Animals were tested in an open-field test, then sacrificed and their striata used for analyses of dopaminergic indices. Results were as follows. The administration of AEA or THC produced the expected inhibition of motor behavior. Thus, the administration of AEA decreased the ambulation and the frequency of stereotypic movements (in particular, the number of rears) and increased the time spent by the rats in inactivity. These effects were evident at 10 and 30 min after the administration of the cannabinoid agonist, but mostly disappeared at 60 min. Interestingly, motor inhibition was observed again around 2 or 3 h after the administration of AEA. This was a small but persistent effect (decreased ambulation followed by increased inactivity), because it was observed until at least 6 h after AEA administration. The other cannabimimetic, THC, was always able of decreasing the ambulation and the frequency of rearing and grooming behavior, and of increasing the time spent in inactivity. This effect was usually something more marked than the effect of AEA, but the most characteristic fact was its persistence at all times studies, even at 6 h after administration. These motor disturbances were accompanied by changes in the activity of nigrostriatal dopaminergic neurons. Thus, the administration of AEA decreased the activity of tyrosine hydroxylase (TH) in the striatum at 10 and 30 min after treatment, suggesting a decreased nigrostriatal activity parallel to the motor deficit observed at these times. This was followed by an increase in TH activity and dopamine and L-3,4-dihydroxyphenylacetic acid contents at 60 min after treatment, which would likely reflect a compensatory stimulation of these neurons, whereas restoration of control values was found at 180 min after AEA administration, suggesting that the motor deficit observed at this time was not dependent on dopaminergic influence. Paradoxically, the administration of THC only produced changes in dopaminergic activity at 60 min after treatment, similar to those seen with AEA, but was ineffective at the other times. In summary, A-EA inhibits motor behavior in parallel to reductions in the activity of nigrostriatal dopaminergic neurons. However, this effect was of short duration, disappearing at 60 min after treatment, as compared with the inhibitory effect of THC on motor behavior which was observed at all times studied. Interestingly, a new AEA-induced inhibition of motor behavior, which was not accompanied by dopaminergic changes, appeared at longer times although its meaning remains to be determined.
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PMID:Time-course of the effects of anandamide, the putative endogenous cannabinoid receptor ligand, on extrapyramidal function. 897 49

Anandamide amidase (EC 3.5.1.4) is responsible for the hydrolysis of arachidonoyl ethanolamide (anandamide). Relatively selective and potent enzyme reversible inhibitors effective in the low micromolar range, such as arachidonyl trifluoromethyl ketone (Arach-CF3), have been described (Koutek et al., J Biol Chem 269: 22937-22940, 1994). In the current study, methyl arachidonyl fluorophosphonate (MAFP), an arachidonyl binding site directed phosphonylation reagent, was tested as an inhibitor of anandamide amidase and as a ligand for the CB1 cannabinoid receptor. MAFP was 800 times more potent than Arach-CF3 and phenylmethylsulfonyl fluoride (PMSF) as an amidase inhibitor in rat brain homogenates. In intact neuroblastoma cells, MAFP was also approximately 1000-fold more potent than Arach-CF3. MAFP demonstrated selectivity towards anandamide amidase for which it was approximately 3000 and 30,000-fold more potent than it was towards chymotrypsin and trypsin, respectively. MAFP displaced [3H]CP-55940 binding to the CB1 cannabinoid receptor with an IC50 of 20 nM vs 40 nM for anandamide. It bound irreversibly and prevented subsequent binding of the cannabinoid radioligand [3H]CP-55940 at that locus. These studies suggest that MAFP is a potent and specific inhibitor of anandamide amidase and, in addition, can interact with the cannabinoid receptors at the cannabinoid binding site. This is the first report of a potent and relatively selective irreversible inhibitor of arachidonoyl ethanolamide amidase.
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PMID:Methyl arachidonyl fluorophosphonate: a potent irreversible inhibitor of anandamide amidase. 906 28

A simple and selective method for the determination of anandamide (arachidonoylethanolamide), an endogenous cannabinoid receptor ligand, and its analogs with liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (LC-APCI-MS) was developed. The calibration curve for standard anandamide was linear over the range 625 fmol-125 pmol per injection (r = 0.999) with a precision of 1.0% (C.V.) at 25 pmol. The detection limit attained was 200 fmol per injection at a signal-to-noise ratio of 2. Anandamide and its analogs were extracted from rat brain and peripheral tissues according to the method of Folch, and the recovery of anandamide from rat brain homogenates was 67.0-72.6%. The method was applied to their determination in rat brain and peripheral tissues.
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PMID:Liquid chromatographic-atmospheric pressure chemical ionization mass spectrometric determination of anandamide and its analogs in rat brain and peripheral tissues. 910 24

The endogenous ligand for the cannabinoid receptor, arachidonylethanolamide (anandamide), has been shown to produce antinociception using the tail-flick test following intrathecal administration. Anandamide was administered i.p. (40 mg kg) to mice four times per day for 3 days. Tolerance developed to anandamide: the ED50 for anandamide (i.t.) was shifted from 40 (26-61) to 139 (79-248) micrograms/mouse. Anandamide-tolerant mice were cross-tolerant to delta 9-THC and CP55,940, but not cross-tolerant to mu-, delta- or kappa- opioids, including dynorphins. Conversely, delta 9-THC-tolerant mice are cross-tolerant to anandamide, CP55,940 and kappa agonists. Our data indicate that anandamide and delta 9-THC differ in the mechanisms by which they induce tolerance, in particular the interaction with endogenous dynorphinergic systems.
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PMID:Characterization of anandamide-induced tolerance: comparison to delta 9-THC-induced interactions with dynorphinergic systems. 917 5

Astrocytes are an important cell population in the CNS, involved in cytokine homeostasis and participating in a variety of important physiological and pathological processes. In the present study we showed that primary cultures of neonatal mouse cortical astrocytes stimulated with lipopolysaccharide (Balb/c mice strain, LPS: 1 microgram/ml, 18 h) or Theiler's virus, TMEV (SJL/J mice strain, TMEV: 10(5) PFU/well, 24 h) released an increased amount of nitrites (NO2-) and tumour necrosis factor-alpha (TNF-alpha) into the culture medium. Exogenous cannabinoids are known to modulate the function of immune cells. Anandamide, an endogenous ligand for the cannabinoid receptor, blocked the release of NO2- and TNF-alpha induced by LPS in a dose-dependent manner. In TMEV-stimulated astrocytes anandamide also suppressed, in a dose-related manner, the stimulatory effects of TMEV on both NO2- and TNF-alpha. It is suggested that anandamide exerts an immunoregulatory role in the CNS. These results could have important implications in the modulation of immunological and inflammatory processes by cannabinoid agents.
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PMID:Anandamide suppresses nitric oxide and TNF-alpha responses to Theiler's virus or endotoxin in astrocytes. 922 79

N-Arachidonoylethanolamine (anandamide, AEA) is a putative endogenous ligand of the cannabinoid receptor. Intact cerebellar granule neurons in primary culture rapidly accumulate AEA. [3H]AEA accumulation by cerebellar granule cells is dependent on incubation time (t(1/2) of 2.6 +/- 0.8 min at 37 degrees C) and temperature. The accumulation of AEA is saturable and has an apparent Km of 41 +/- 15 microM and a Vmax of 0.61 +/- 0.04 nmol/min/10(6) cells. [3H]AEA accumulation by cerebellar granule cells is significantly reduced by 200 microM phloretin (57.4 +/- 4% of control) in a noncompetitive manner. [3H]AEA accumulation is not inhibited by either ouabain or removal of extracellular sodium. [3H]AEA accumulation is fairly selective for AEA among other naturally occurring N-acylethanolamines; only N-oleoylethanolamine significantly inhibited [3H]AEA accumulation at a concentration of 10 microM. The ethanolamides of palmitic acid and linolenic acid were inactive at 10 microM. N-Arachidonoylbenzylamine and N-arachidonoylpropylamine, but not arachidonic acid, 15-hydroxy-AEA, or 12-hydroxy-AEA, compete for AEA accumulation. When cells are preloaded with [3H]AEA, temperature-dependent efflux occurs with a half-life of 1.9 +/- 1.0 min. Phloretin does not inhibit [3H]AEA efflux from cells. These results suggest that AEA is accumulated by cerebellar granule cells by a protein-mediated transport process that has the characteristics of facilitated diffusion.
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PMID:Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion. 923 21

We recently demonstrated that the gene encoding the peripheral cannabinoid receptor (Cb2) may be a proto-oncogene involved in murine myeloid leukemias. We show here that Cb2 may have a role in hematopoietic development. RNAse protection analysis showed that Cb2 is normally expressed in spleen and thymus. Cb2 mRNA is also expressed in 45 of 51 cell lines of distinct hematopoietic lineages, ie, myeloid, macrophage, mast, B-lymphoid, T-lymphoid, and erythroid cells. The effect of the fatty acid anandamide, an endogenous ligand for cannabinoid receptors, on primary murine marrow cells and hematopoietic growth factor (HGF)-dependent cell lines was then investigated. In vitro colony cultures of normal mouse bone marrow cells showed anandamide to potentiate interleukin-3 (IL-3)-induced colony growth markedly. Whereas HGFs alone stimulate proliferation of the various cell lines in serum-free culture only weakly, anandamide enhances the proliferative response of the cell lines to HGFs profoundly. This was apparent for responses induced by IL-3, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin. Anandamide was already effective at concentrations as low as 0.1 to 0.3 micromol/L and plateau effects were reached at 0.3 to 3 micromol/L. The addition of anandamide as single growth factor had no effect. The costimulatory effect of anandamide was not evident when cells were cultured with fetal calf serum (FCS), suggesting that FCS contains anandamide or another ligand capable of activating the peripheral cannabinoid receptor. Other cannabinoid ligands did not enhance the proliferative responsiveness of hematopoietic cells to HGFs. Transfection experiments of Cb2 in myeloid 32D cells showed that anandamide specifically activates proliferation through activation of the peripheral cannabinoid receptor. Anandamide appears to be a novel and synergistic growth stimulator for hematopoietic cells.
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PMID:Anandamide, a natural ligand for the peripheral cannabinoid receptor is a novel synergistic growth factor for hematopoietic cells. 926 62

Morphine and anandamide stimulate the release of nitric oxide (NO) in diverse tissues. The present study examines the consequences of this action on neurotransmitter release in ganglia from two invertebrates: ventral chain ganglia from the leech Hirudo medicinalis and the pedal ganglion from the mussel Mytilus edulis. In these ganglia, preloaded serotonin (5-HT) and dopamine (DA) can be released by 50 mM KCl. Anandamide, an endogenous cannabinoid substance, suppresses the potassium-stimulated release of [3H]DA (80%), but not 5-HT, in a concentration-dependent manner, from the neural tissues of both. The effect of anandamide can be antagonized by pre-exposing the neural tissues of both animals to SR 141716A, a potent cannabinoid receptor antagonist. Prior treatment of the ganglia with N-omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, significantly diminishes the inhibitory effect of anandamide. Morphine also inhibits [3H]DA release in a naloxone- and L-NAME-sensitive manner. Anandamide and morphine act through separate mechanisms since the respective antagonists show no cross-reactivity. The NO donor, SNAP, depressed the potassium-stimulated release of preloaded [3H]DA, but not 5-HT, in the neural tissues of both animals. D-Ala2-Met5 enkephalinamide (DAMA) also inhibited the potassium-stimulated release of [3H]DA in a naloxone-sensitive process. However, the effect of DAMA was seen in the presence of L-NAME (10(-4) M), indicating that the opioid peptide inhibition of the presynaptic release of DA is not coupled to NO. We postulate that cannabinoids and their endogenous effectors play a prominent role in the regulation of catecholamine release in invertebrates via NO release as is the case for opiate alkaloids.
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PMID:Morphine- and anandamide-stimulated nitric oxide production inhibits presynaptic dopamine release. 927 29

The endogenous cannabinoid receptor agonist anandamide is present in central and peripheral tissues. As the kidney contains both the amidase that degrades anandamide and transcripts for anandamide receptors, we characterized the molecular components of the anandamide signaling system and the vascular effects of exogenous anandamide in the kidney. We show that anandamide is present in kidney homogenates, cultured renal endothelial cells (EC), and mesangial cells; these cells also contain anandamide amidase. Reverse-transcriptase PCR shows that EC contain transcripts for cannabinoid type 1 (CB1) receptors, while mesangial cells have mRNA for both CB1 and CB2 receptors. EC exhibit specific, high-affinity binding of anandamide (Kd = 27.4 nM). Anandamide (1 microM) vasodilates juxtamedullary afferent arterioles perfused in vitro; the vasodilation can be blocked by nitric oxide (NO) synthase inhibition with L-NAME (0.1 mM) or CB1 receptor antagonism with SR 141716A (1 microM), but not by indomethacin (10 microM). Anandamide (10 nM) stimulates CB1-receptor-mediated NO release from perfused renal arterial segments; a similar effect was seen in EC. Finally, anandamide (1 microM) produces a NO-mediated inhibition of KCl-stimulated [3H]norepinephrine release from sympathetic nerves on isolated renal arterial segments. Hence, an anandamide signaling system is present in the kidney, where it exerts significant vasorelaxant and neuromodulatory effects.
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PMID:Production and physiological actions of anandamide in the vasculature of the rat kidney. 929 22

1. Relaxation of the methoxamine-precontracted rat small mesenteric artery by endothelium-derived hyperpolarizing factor (EDHF) was compared with relaxation to the cannabinoid, anandamide (arachidonylethanolamide). EDHF was produced in a concentration- and endothelium-dependent fashion in the presence of NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) by either carbachol (pEC50 [negative logarithm of the EC50] = 6.19 +/- 0.01, Rmax [maximum response] = 93.2 +/- 0.4%; n = 14) or calcium ionophore A23187 (pEC50 = 6.46 +/- 0.02, Rmax = 83.6 +/- 3.6%; n = 8). Anandamide responses were independent of the presence of endothelium or L-NAME (control with endothelium: pEC50 = 6.31 +/- 0.06, Rmax = 94.7 +/- 4.6%; n = 10; with L-NAME: pEC50 = 6.33 +/- 0.04, Rmax = 93.4 +/- 6.0%; n = 4). 2. The selective cannabinoid receptor antagonist, SR 141716A (1 microM) caused rightward shifts of the concentration-response curves to both carbachol (2.5 fold) and A23187 (3.3 fold). It also antagonized anandamide relaxations in the presence or absence of endothelium giving a 2 fold shift in each case. SR 141716A (10 microM) greatly reduced the Rmax values for EDHF-mediated relaxations to carbachol (control, 93.2 +/- 0.4%; SR 141716A, 10.7 +/- 2.5%; n = 5; P < 0.001) and A23187 (control, 84.8 +/- 2.1%; SR 141716A, 3.5 +/- 2.3%; n = 6; P < 0.001) but caused a 10 fold parallel shift in the concentration-relaxation curve for anandamide without affecting Rmax. 3. Precontraction with 60 mM KCl significantly reduced (P < 0.01; n = 4 for all) relaxations to 1 microM carbachol (control 68.8 +/- 5.6% versus 17.8 +/- 7.1%), A23187 (control 71.4 +/- 6.1% versus 3.9 +/- 0.45%) and anandamide (control 71.1 +/- 7.0% versus 5.2 +/- 3.6%). Similar effects were seen in the presence of 25 mM K+. Incubation of vessels with pertussis toxin (PTX; 400 ng ml-1, 2 h) also reduced (P < 0.01; n = 4 for all) relaxations to 1 microM carbachol (control 63.5 +/- 7.5% versus 9.0 +/- 3.2%), A23187 (control 77.0 +/- 5.8% versus 16.2 +/- 7.1%) and anandamide (control 89.8 +/- 2.2% versus 17.6 +/- 8.7%). 4. Incubation of vessels with the protease inhibitor phenylmethylsulphonyl fluoride (PMSF; 200 microM) significantly potentiated (P < 0.01), to a similar extent (approximately 2 fold), relaxation to A23187 (pEC50: control, 6.45 +/- 0.04; PMSF, 6.74 +/- 0.10; n = 4) and anandamide (pEC50: control, 6.31 +/- 0.02; PMSF, 6.61 +/- 0.08; n = 8). PMSF also potentiated carbachol responses both in the presence (pEC50: control, 6.25 +/- 0.01; PMSF, 7.00 +/- 0.01; n = 4; P < 0.01) and absence (pEC50: control, 6.41 +/- 0.04; PMSF, 6.88 +/- 0.04; n = 4; P < 0.001) of L-NAME. Responses to the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) were also potentiated by PMSF (pEC50: control, 7.51 +/- 0.06; PMSF, 8.00 +/- 0.05, n = 4, P < 0.001). 5. EDHF-mediated relaxation to carbachol was significantly attenuated by the K+ channel blocker tetraethylammonium (TEA; 1 mM) (pEC50: control, 6.19 +/- 0.01; TEA, 5.61 +/- 0.01; n = 6; P < 0.01). In contrast, TEA (1 mM) had no effect on EDHF-mediated relaxation to A23187 (pEC50: control, 6.47 +/- 0.04; TEA, 6.41 +/- 0.02, n = 4) or on anandamide (pEC50: control, 6.28 +/- 0.06; TEA, 6.09 +/- 0.02; n = 5). TEA (10 mM) significantly (P < 0.01) reduced the Rmax for anandamide (control, 94.3 +/- 4.0%; 10 mM TEA, 60.7 +/- 4.4%; n = 5) but had no effect on the Rmax to carbachol or A23187. 6. BaCl2 (100 microM), considered to be selective for blockade of inward rectifier K+ channels, had no significant effect on relaxations to carbachol or A23187, but caused a small shift in the anandamide concentration-response curve (pEC50: control, 6.39 +/- 0.01; Ba2+, 6.20 +/- 0.01; n = 4; P < 0.01). BaCl2 (1 mM; which causes non-selective block of K+ channels) significantly (P < 0.01) attenuated relaxations to all three agents (pEC50 values: carbachol, 5.65 +/- 0.02; A23187, 5.84 +/- 0.04; anandamide, 5.95 +/- 0.02; n = 4 for each). 7. Apamin (1mu M), a selective blocker of small conductance, Ca2+-activated, K+ channels (SKCa), 4-aminopyridine (1mM), a blocker of delayed rectifier, voltage-dependent, K+ channels (Kv), and ciclazindol (10mu M), an inhibitor of Kv and adenosine 5'-triphosphate (ATP)-sensitive K+ channels (KATP), significantly reduced EDHF-mediated relaxations to carbachol, but had no significant effects on A23187 or anandamide responses. 8. Glibenclamide (10mu M), a KATP inhibitor and charybdotoxin (100 or 300nM), a blocker of several K+ channel subtypes, had no significant effect on relaxations to any of the agents. Iberiotoxin (50nM), an inhibitor of large conductance, Ca2+-activated, K+ channels (BKCa), had no significant effect on the relaxation responses, either alone or in combination with apamin (1muM). Also, a combination of apamin (1muM) with either glibenclamide (10muM) or 4-aminopyridine (1mM) did not inhibit relaxation to carbachol significantly more than apamin alone. Neither combination had any significant effect on relaxation to A23187 or anandamide. 9. A combination of apamin (1muM) with charybdotoxin (100nM) abolished EDHF-mediated relaxation to carbachol, but had no significant effect on that to A23187. Apamin (1muM) and charybdotoxin (300nM) together consistently inhibited the response to A23187, while apamin (1muM) and ciclazindol (10muM) together inhibited relaxations to both carbachol and A23187. None of these toxin combinations had any significant effect on relaxation to anandamide. 10. It was concluded that the differential sensitivity to K+ channel blockers of EDHF-mediated responses to carbachol and A23187 might be due to actions on endothelial generation of EDHF, as well as its actions on the vascular smooth muscle, and suggests care must be taken in choosing the means of generating EDHF when making comparative studies. Also, the relaxations to EDHF and anandamide may involve activation of cannabinoid receptors, coupled via PTX-sensitive G-proteins to activation of K+ conductances. The results support the hypothesis that EDHF is an endocannabinoid but relaxations to EDHF and anandamide show differential sensitivity to K+ channel blockers, therefore it is likely that anandamide is not identical to EDHF in the small rat mesenteric artery.
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PMID:A comparison of EDHF-mediated and anandamide-induced relaxations in the rat isolated mesenteric artery. 942 1


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