UNIPROT:P21554 - FACTA Search

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

The effects of two cannabinoid receptor agonists, R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4- benzoxazin-yl]-(1-naphthalenyl)-methanone (WIN 55,212-2) and (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydr oxypropyl)-cyclohexanol (CP-55,940), were studied on (i) the vasopressor response elicited in pithed rats by electrical stimulation of the sympathetic outflow and (ii) the release of 3H-noradrenaline and the vasoconstriction elicited in isolated rat tail arteries by transmural electrical stimulation. In pithed rats, the electrical (1 Hz for 10 s) stimulation of the preganglionic sympathetic nerve fibres increased diastolic blood pressure by about 30 mmHg. This neurogenic vasopressor response (which under the conditions of our study was almost exclusively due to the release of catecholamines) was decreased by WIN 55-212,2 and CP-55,940 in a dose-dependent manner (inhibition by WIN 55,212-2 and CP-55,940, 0.1 micromol/kg each, about 25-30%). The inhibition was identical in adrenalectomized rats and in animals with intact adrenals. The inhibitory action of WIN 55,212-2 and CP-55,940 was abolished by a dose of 0.03 micromol/kg of the CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazo le-carboxamide (SR 141716), which, by itself, had no effect. WIN 55,212-2, CP-55,940 and SR 141716 failed to affect the vasopressor response to exogenous noradrenaline (1 nmol/kg), which also increased diastolic blood pressure by about 30 mmHg. In isolated rat tail arteries, the electrically (0.4 Hz) evoked tritium overflow and vasoconstriction were not modified by WIN 55,212-2 and CP-55,940 (1 micromol/l each). In conclusion, the neurogenic vasopressor response in the pithed rat can be modulated via cannabinoid CB1 receptors probably located presynaptically on the postganglionic sympathetic nerve fibres innervating resistance vessels.
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PMID:Cannabinoid CB1 receptor-mediated inhibition of the neurogenic vasopressor response in the pithed rat. 927 25

SR 141716, a selective central CB1 cannabinoid receptor antagonist, markedly and selectively reduces sucrose feeding and drinking as well as neuropeptide Y-induced sucrose drinking in rats. SR 141716 also decreases ethanol consumption in C57BL/6 mice. In contrast, blockade of CB1 receptors only marginally affects regular chow intake or water drinking. The active doses of SR 141716 (0.3-3 mg/kg) are in the range known to antagonize the characteristic effects induced by cannabinoid receptor agonists. These results suggest for the first time that endogenous cannabinoid systems may modulate the appetitive value of sucrose and ethanol, perhaps by affecting the activity of brain reward systems.
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PMID:Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. 927 66

Using the endogenous cannabinoid receptor agonist anandamide, the synthetic agonist CP 55940 [[1alpha,2beta(R)5alpha]-(-)-5-(1,1-dimethylheptyl+ ++)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol], and the specific antagonist SR 141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride], second messenger activation of the central cannabinoid receptor (CB1) was examined in rat striatal and cortical slices. The effects of these cannabinoid ligands on electrically evoked dopamine (DA) release from [3H] dopamine-prelabelled striatal slices were also investigated. CP 55940 (1 microM) and anandamide (10 microM) caused significant reductions in forskolin-stimulated cyclic AMP accumulation in rat striatal slices, which were reversed in the presence of SR 141716 (1 microM). CP 55940 (1 microM) had no effect on either KCl- or neurotransmitter-stimulated 3H-inositol phosphate accumulation in rat cortical slices. CP 55940 and anandamide caused significant reductions in the release of dopamine after electrical stimulation of [3H]dopamine-prelabelied striatal slices, which were antagonised by SR 141716. SR 141716 alone had no effect on electrically evoked dopamine release from rat striatal slices. These data indicate that the CB1 receptors in rat striatum are negatively linked to adenylyl cyclase and dopamine release. That the CB1 receptor may influence dopamine release in the striatum suggests that cannabinoids play a modulatory role in dopaminergic neuronal pathways.
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PMID:Influence of cannabinoids on electrically evoked dopamine release and cyclic AMP generation in the rat striatum. 928 35

Arachidonyl ethanolamide, anandamide (ANA) was administered to male rats via a single i.p. injection at a dose of 0.02 mg/kg. In an parallel experiment ANA injection was preceded by the injection of SR 141716 (1.0 mg/kg), a selective and potent cannabinoid receptor antagonist. We observed using FOS protein immunocytochemistry that the parvocellular part of hypothalamic paraventricular nucleus (PVN) was activated as soon as 45 min. after ANA injection, i.e. the PVN showed an increased FOS immunoreactivity (FOSir). The peak level of FOSir was observed 90 min, after treatment. Meanwhile serum ACTH and corticosterone levels, as measured by radioimmunoassay, also significantly increased. 180 min. following drug injection both FOSir and serum hormone levels and returned to normal. SR 141716 did not antagonize these effects of ANA. We postulate that the locus of action of ANA the activation of the hypothalamo-pituitary-adrenal (HPA) axis is the parvocellular part of PVN. This activation may occur via a possible central cannabinoid receptor for which SR 141716 is not an effective antagonist. The rapid central response and activation of the HPA axis further support the view that ANA may be a central neurotransmitter or neuromodulator.
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PMID:Arachidonyl ethanolamide (anandamide) activates the parvocellular part of hypothalamic paraventricular nucleus. 929 34

We examined the question of whether cannabinoid receptors modulating noradrenaline release are detectable in the brain of humans and experimental animals. For this purpose, hippocampal slices from humans, guinea-pigs, rats and mice and cerebellar, cerebrocortical and hypothalamic slices from guinea-pigs were incubated with [3H]noradrenaline and then superfused. Tritium overflow was evoked either electrically (0.3 or 1 Hz) or by introduction of Ca2+ ions (1.3 mM) [corrected] into Ca(2+)-free, K(+)-rich medium (25 mM) [corrected] containing tetrodotoxin 1 microM. Furthermore, the cAMP accumulation stimulated by forskolin 10 microM was determined in guinea-pig hippocampal membranes. We used the following drugs: the cannabinoid receptor agonists (-)-cis-3-[2-hydroxy-4-(1,1- dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclo-hexanol (CP-55,940) and R(+)-[2,3-dihydro-5-methyl-3- [(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]- (1-naphthalenyl)methanone (WIN 55,212-2), the inactive S(-)-enantiomer of the latter (WIN 55,212-3) and the CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)- 1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR 141716). The electrically evoked tritium overflow from guinea-pig hippocampal slices was reduced by WIN 55,212-2 (pIC30% 6.5) but not affected by WIN 55,212-3 up to 10 microM. The concentration-response curve of WIN 55,212-2 was shifted to the right by SR 141716 (0.032-microM) (apparent pA2 8.2), which by itself did not affect the evoked overflow. WIN 55,212-2 1 microM also inhibited the Ca(2+)-evoked tritium overflow in guinea-pig hippocampal slices and the electrically evoked overflow in guinea-pig cerebellar, cerebrocortical and hypothalamic slices as well as in human hippocampal slices but not in rat and mouse hippocampal slices. SR 141716 (0.32 microM) markedly attenuated the WIN 55,212-2-induced inhibition in guinea-pig and human brain slices. SR 141716 0.32 microM by itself increased the electrically evoked tritium overflow in guinea-pig hippocampal slices but failed to do so in slices from the other brain regions of the guinea-pig and in human hippocampal slices but failed to do so in slices from the other brain regions of the guinea-pig and in human hippocampal slices. The cAMP accumulation stimulated by forskolin was reduced by CP-55,940 and WIN 55,212-2. The concentration-response curve of CP 55,940 was shifted to the right by SR 141716 (0.1 microM; apparent pA2 8.3), which by itself did not affect cAMP accumulation. In conclusion, cannabinoid receptors of the CB1 subtype occur in the human hippocampus, where they may contribute to the psychotropic effects of cannabis, and in the guinea-pig hippocampus, cerebellum, cerebral cortex and hypothalamus. The CB1 receptor in the guinea-pig hippocampus is located presynaptically, is activated by endogenous cannabinoids and may be negatively coupled to adenylyl cyclase.
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PMID:Cannabinoid CB1 receptor-mediated inhibition of noradrenaline release in the human and guinea-pig hippocampus. 940 37

1. The purpose of these experiments was to determine whether or not the endothelium-dependent hyperpolarizations of the vascular smooth muscle cells (observed in the presence of inhibitors of nitric oxide synthase and cyclo-oxygenase) can be attributed to the production of an endogenous cannabinoid. 2. Membrane potential was recorded in the guinea-pig carotid, rat mesenteric and porcine coronary arteries by intracellular microelectrodes. 3. In the rat mesenteric artery, the cannabinoid receptor antagonist, SR 141716 (1 microM), did not modify either the resting membrane potential of smooth muscle cells or the endothelium-dependent hyperpolarization induced by acetylcholine (1 microM) (17.3 +/- 1.8 mV, n = 4 and 17.8 +/- 2.6 mV, n = 4, in control and presence of SR 141716, respectively). Anandamide (30 microM) induced a hyperpolarization of the smooth muscle cells (12.6 +/- 1.4 mV, n = 13 and 2.0 +/- 3.0 mV, n = 6 in vessels with and without endothelium, respectively) which could not be repeated in the same tissue, whereas acetylcholine was still able to hyperpolarize the preparation. The hyperpolarization induced by anandamide was not significantly influenced by SR 141716 (1 microM). HU-210 (30 microM), a synthetic CB1 receptor agonist, and palmitoylethanolamide (30 microM), a CB2 receptor agonist, did not influence the membrane potential of the vascular smooth muscle cells. 4. In the rat mesenteric artery, the endothelium-dependent hyperpolarization induced by acetylcholine (1 microM) (19.0 +/- 1.7 mV, n = 6) was not altered by glibenclamide (1 microM; 17.7 +/- 2.3 mV, n = 3). However, the combination of charybdotoxin (0.1 microM) plus apamin (0.5 microM) abolished the acetylcholine-induced hyperpolarization and under these conditions, acetylcholine evoked a depolarization (7.7 +/- 2.7 mV, n = 3). The hyperpolarization induced by anandamide (30 microM) (12.6 +/- 1.4 mV, n = 13) was significantly inhibited by glibenclamide (4.0 +/- 0.4 mV, n = 4) but not significantly affected by the combination of charybdotoxin plus apamin (17.3 +/- 2.3 mV, n = 4). 5. In the guinea-pig carotid artery, acetylcholine (1 microM) evoked endothelium-dependent hyperpolarization (18.8 +/- 0.7 mV, n = 15). SR 141716 (10 nM to 10 microM), caused a direct, concentration-dependent hyperpolarization (up to 10 mV at 10 microM) and a significant inhibition of the acetylcholine-induced hyperpolarization. Anandamide (0.1 to 3 microM) did not influence the membrane potential. At a concentration of 30 microM, the cannabinoid agonist induced a non-reproducible hyperpolarization (5.6 +/- 1.3 mV, n = 10) with a slow onset. SR 141716 (1 microM) did not affect the hyperpolarization induced by 30 microM anandamide (5.3 +/- 1.5 mV, n = 3). 6. In the porcine coronary artery, anandamide up to 30 microM did not hyperpolarize or relax the smooth muscle cells. The endothelium-dependent hyperpolarization and relaxation induced by bradykinin were not influenced by SR 141716 (1 microM). 7. These results indicate that the endothelium-dependent hyperpolarizations, observed in the guinea-pig carotid, rat mesenteric and porcine coronary arteries, are not related to the activation of cannabinoid CB1 receptors.
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PMID:Cannabinoid CB1 receptor and endothelium-dependent hyperpolarization in guinea-pig carotid, rat mesenteric and porcine coronary arteries. 953 27

The involvement of cannabinoid processes in positive reinforcement was studied using an unbiased, one-compartment, conditioned place preference (CPP) procedure in rats. This was achieved by examining the ability of the selective antagonist of the CB1 cannabinoid receptor subtype, SR 141716, to counteract the CPP supported by classical reinforcers. The acquisition of CPP induced by cocaine (2 mg/kg), morphine (4 mg/kg) and food (standard chow and sucrose pellets) was dose-dependently blocked by pre-pairing administration of SR 141716 (0.03-3 mg/kg). However, SR 141716 (up to 10 mg/kg) did not significantly counteract the expression of cocaine-induced CPP. On the other hand, the synthetic CB receptor agonist, WIN 55212-2 (0.3-1 mg/kg), established a robust place aversion (CPA), as already described with other agonists, and CPP was never observed, even at 100-fold lower doses. The aversive effect of WIN 55212-2 was reversed by SR 141716 (0.3-1 mg/kg), suggesting that it was accounted for by the stimulation of CB1 receptors. These findings indicate that, on their own, CB receptor agonists are unable to generate the processes necessary to induce a pleasurable state in animals, as assessed in place conditioning procedures. Nevertheless, a cannabinoid link may be involved in the neurobiological events, allowing the perception of the rewarding value of various kinds of reinforcers. However, a permanent endogenous cannabinoid tone seems unlikely to be necessary to ensure the organism a basal hedonic level since, given alone, SR 141716 supported neither CPP nor CPA.
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PMID:Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats. 953 55

The effects of cannabinoids on metabolic pathways and signal transduction systems were studied in primary cultures of rat astrocytes. Delta9-Tetrahydrocannabinol (THC), the major active component of marijuana, increased the rate of glucose oxidation to CO2 as well as the rate of glucose incorporation into phospholipids and glycogen. These effects of THC were mimicked by the synthetic cannabinoid HU-210, and prevented by forskolin, pertussis toxin, and the CB1 receptor antagonist SR 141716. THC did not affect basal cAMP levels but partially antagonized the forskolin-induced elevation of intracellular cAMP concentration. THC stimulated p42/p44 mitogen-activated protein kinase (MAPK) activity, Raf-1 phosphorylation, and Raf-1 translocation to the particulate cell fraction. In addition, the MAPK inhibitor PD 098095 and the phosphoinositide 3-kinase inhibitors wortmannin and LY 294002 were able to antagonize the THC-induced stimulation of glucose oxidation to CO2, phospholipid synthesis and glycogen synthesis. The possible involvement of sphingomyelin breakdown in the metabolic effects of THC was studied subsequently. THC produced a rapid stimulation of sphingomyelin hydrolysis that was concomitant to an elevation of intracellular ceramide levels. This effect was prevented by SR 141716. Moreover, the cell-permeable ceramide analog D-erythro-N-octanoylsphingosine, as well as exogenous sphingomyelinase, were able in turn to stimulate MAPK activity, to increase the amount of Raf-1 bound to the particulate cell fraction, and to stimulate glucose metabolism. The latter effect was prevented by PD 098059 and was not additive to that exerted by THC. Results thus indicate that THC produces a cannabinoid receptor-mediated stimulation of astrocyte metabolism that seems to rely on sphingomyelin hydrolysis and MAPK stimulation.
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PMID:Involvement of sphingomyelin hydrolysis and the mitogen-activated protein kinase cascade in the Delta9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes. 980 18

Delta9-tetrahydrocannabinol (Delta9-THC) is the principal psychoactive ingredient in marijuana. We examined the effects of Delta9-THC on glutamatergic synaptic transmission. Reducing the extracellular Mg++ concentration bathing rat hippocampal neurons in culture to 0.1 mM elicited a repetitive pattern of glutamatergic synaptic activity that produced intracellular Ca++ concentration spikes that were measured by indo-1-based microfluorimetry. Delta9-THC produced a concentration-dependent inhibition of spike frequency with an EC50 of 20 +/- 4 nM and a maximal inhibition of 41 +/- 3%. Thus, Delta9-THC was potent, but had low intrinsic activity. Delta9-THC (100 nM) inhibition of spiking was reversed by 300 nM N-piperidino-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR 141716), indicating that the inhibition was mediated by CB1 cannabinoid receptors. Delta9-THC attenuated the inhibition produced by a full cannabinoid receptor agonist, (+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo-[1,2,3-de]-1, 4-benzoxazin-6-yl](1-napthalenyl)methanone monomethanesulfonate (Win 55212-2), indicating that Delta9-THC is a partial agonist. The effect of Delta9-THC on synaptic currents was also studied. 6-Cyano-2,3-dihydroxy-7-niroquiinoxaline (CNQX)-sensitive excitatory postsynaptic currents were recorded from cells held at -70 mV in the whole-cell configuration of the patch-clamp and elicited by presynaptic stimulation with an extracellular electrode. Win 55212-2 and Delta9-THC inhibited excitatory postsynaptic current (EPSC) amplitude by 96 +/- 2% and 57 +/- 4%, respectively. Excitatory postsynaptic current amplitude was reduced to 75 +/- 5% in the presence of both drugs, demonstrating that Delta9-THC is a partial agonist. The psychotropic effects of Delta9-THC may result from inhibition of glutamatergic synaptic transmission. The modest physical dependence produced by Delta9-THC as well as its lack of acute toxicity may be due to the ability of the drug to reduce, but not block, excitatory neurotransmission.
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PMID:Delta9-tetrahydrocannabinol acts as a partial agonist to modulate glutamatergic synaptic transmission between rat hippocampal neurons in culture. 988 92

We have studied the effect of SR141716A (0.1-5 mg/kg, i.p.), a cannabinoid CB, receptor antagonist, and WIN (0.1-5 mg/kg, i.p.), a cannabinoid receptor agonist, on acute defaecation and gastrointestinal transit in mice and on intraluminal fluid accumulation in the rat small intestine. SR141716A increased while WIN 55,212-2 decreased defaecation, gastrointestinal transit and fluid accumulation. A per se non-effective dose of SR141716A (0.3 mg/kg) counteracted the inhibitory effect of WIN 55,212-2 (1 mg/kg) on gastrointestinal functions studied. The effect of SR 141716 on both intestinal fluid accumulation in rats and gastrointestinal transit in mice was inhibited by atropine (1 mg/kg, i.p.), but not by hexamethonium (1 mg/kg, s.c.), SR140333 (20 microg/kg, i.p.) or SR48968 (20 microg/kg, i.p.), antagonists of NK1 and NK2 receptors, respectively. These results suggest that intestinal fluid accumulation and motility are inhibited by endogenous cannabinoid(s) acting at the cannabinoid CB1 receptors. This effect may be mediated by mechanisms involving muscarinic cholinoceptors.
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PMID:Defaecation, intestinal fluid accumulation and motility in rodents: implications of cannabinoid CB1 receptors. 993 53

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