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

To characterize the time course of the behavioral and biochemical aspects of the cannabinoid withdrawal syndrome, we injected the cannabinoid antagonist SR141716A (5 mg/kg i.p.) in rats made tolerant to CP-55,940 (0.4 mg/kg i.p., twice daily for 6.5 days), 1, 24 and 96 h after the last CP-55,940 injection. Because the CB1 receptor and G protein alpha subunit are involved in cannabinoid tolerance, we observed their changes throughout the brain during the withdrawal syndrome by use of in situ hybridization. In vehicle-pretreated rats SR141716A per se induced abnormal behavior significantly different from the vehicle group: wet dog shakes, forepaw fluttering and scratching. These signs remained significantly elevated even after the second and third antagonist doses. SR141716A significantly modified the mRNA levels of G alpha s and G alpha i subunits in some brain areas without affecting CB1 receptor and G alpha o expression. These findings led us to conclude that SR141716A may have intrinsic activity. Concerning cannabinoid withdrawal, the first SR141716A injection in tolerant rats resulted in behavioral signs different from those observed with the antagonist alone; this moderate withdrawal syndrome was characterized by turning, chewing and digging. Additional SR141716A doses 24 and 96 h later did not induce a significant abstinence syndrome. In situ hybridization after the first SR141716A injection showed that CB1 receptor and G protein alpha subunits, whose levels were low in tolerance, recovered their basal level of expression. Thus, the general desensitization of the cannabinoid receptor and of the transduction system in tolerance are recovered in abstinent rats and might be part of the molecular mechanisms underlying cannabinoid dependence.
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PMID:Cannabinoid-precipitated withdrawal: a time-course study of the behavioral aspect and its correlation with cannabinoid receptors and G protein expression. 958 Jun 31

Marijuana has been in use for over 4000 years as a therapeutic and as a recreational drug. Within the past decade, two cannabinoid receptor types have been identified, their signal transduction characterized, and an endogenous lipid agonist isolated from mammalian tissues. The CB1 cannabinoid receptor is widely distributed in mammalian tissues, with the highest concentrations found in brain neurons. CB1 receptors are coupled to modulation of adenylate cyclase and ion channels. The CB2 receptor is found in cells of the immune system and is coupled to inhibition of adenylate cyclase. Both receptor types selectively bind delta 9-THC, the active principle in marijuana, and anandamide (arachidonylethanolamide), an endogenous cannabimimetic eicosanoid. Progress is being made in the development of novel agonists and antagonists with receptor subtype selectivity, mice with genetic deletion of the cannabinoid receptors, and receptor-specific antibodies, which should help in providing a better understanding of the physiological role of the cannabinoid receptors.
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PMID:Cannabinoid receptors and their endogenous agonists. 959 53

Little is known about the effectiveness of delta9-tetrahydrocannabinol (THC) and anandamide in blocking mechanical nociception. Even less is known about their antinociceptive efficacy in chronic inflammatory arthritis induced by Freund's complete adjuvant. The hypothesis was tested that THC and anandamide elicit antinociception in the paw pressure test, and that arthritic rats would exhibit a different response. In nonarthritic rats, THC- and anandamide-induced antinociception lasted 90 min and 15 min, respectively, while antinociception lasted 90 min and 30 min, respectively, in arthritic rats. Area under the curve calculations revealed no effect of arthritis on THC- and anandamide-induced antinociception. Another hypothesis was that paw pressure thresholds in arthritic rats reflect chronic cannabinoid receptor stimulation due to elevations in free anandamide levels. Yet, the CB1 receptor antagonist SR141716A failed to alter paw pressure thresholds in either nonarthritic or arthritic rats. Further investigation revealed that SR141716A significantly blocked THC antinociception, with no effect on anandamide. Thus, anandamide's effects did not result from CB1 receptor stimulation, and any potential contribution of endogenous anandamide in arthritis was not revealed. Finally, THC and anandamide appear to release an as yet unknown endogenous opioid, because naloxone significantly blocked their effects. This study indicates that anandamide and THC may act at different receptor sites to modulate endogenous opioid levels in mechanical nociception.
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PMID:Characterization of delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats. 961 Sep 41

Electrophysiological consequences of activation of cannabinoid receptors have been mostly investigated on neuronal cell lines and on cells transfected with cannabinoid receptors. The aim of the present experiments was to study cannabinoid effects on identified neurons in situ. Electrically-evoked postsynaptic currents and voltage-dependent calcium currents were investigated in the principal neurons of the corpus striatum, the medium spiny neurons, with the patch-clamp method for brain slices. These neurons were chosen because they produce messenger RNA for cannabinoid receptors and because the density of cannabinoid binding sites in the striatum is high. Activation of muscarinic receptors by carbachol (10(-5) M) reduced inhibitory postsynaptic current amplitude by 67%. The synthetic cannabinoid receptor agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4- benzoxazin-yl]-(1-naphtalenyl)methanone (WIN55212-2; 10(-8) to 10(-5) M) dose-dependently reduced striatal inhibitory postsynaptic currents; the maximum effect, inhibition by 52%, was observed at 10(-6) M. Another cannabinoid agonist, (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydr oxypropyl)cyclohexanol (CP55940; 10(-6) M), also reduced inhibitory postsynaptic currents, by 50%. The CB1 cannnabinoid receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)4-methyl-3-pyra zolecarboxamide (SR141716A; 10(-6) M) had no effect when given alone but abolished the effect of WIN55212-2 (10(-6) M). WIN55212-2 (10(-6) M) did not change the current evoked by the GABA(A)-receptor agonist muscimol (10(-6) M). Activation of muscarinic receptors by carbachol (10(-5) M) inhibited voltage-dependent calcium currents by 21%, but the cannabinoid receptor agonist WIN55212-2 (10(-6) M) was without effect. The results show that activation of CB1 cannabinoid receptors reduces GABAergic inhibitory postsynaptic currents in medium spiny neurons of the corpus striatum: the likely mechanism is presynaptic inhibition of GABA release from terminals of recurrent axons of the medium spiny neurons themselves.
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PMID:Inhibition of GABAergic inhibitory postsynaptic currents by cannabinoids in rat corpus striatum. 962 39

We have previously reported that intracerebroventricular or intrathecal administration of inactive doses of delta9-tetrahydrocannabinol (THC) greatly enhance the antinociceptive potency of morphine in the mouse tail-flick test. Experiments were conducted to test the hypothesis that morphine's potency would be enhanced in mice receiving THC and morphine by conventional per os (p.o.) and subcutaneously (s.c.) routes of administration. Antinociception was measured in the tail-flick test of radiant heat after administration of different combinations of THC and morphine p.o. and s.c. Subcutaneous administration of THC (4 and 25 mg/kg) increased the potency of s.c. morphine 8.5- and 22.3-fold, respectively, while s.c. THC (25 mg/kg) increased the potency of p.o. morphine 3.1-fold. Per os administration of THC (10 and 20 mg/kg) increased the potency of s.c. and p.o. morphine 11.4-fold and 7.6-fold, respectively. Thus, morphine's potency was significantly increased regardless of the enteral and parenteral routes of THC and morphine administration. The synthetic receptor selective cannabinoid CP-55, 940 (0.1 mg/kg, s.c.) also enhanced morphine's potency. Finally, the ability of the CB1 receptor antagonist SR141716A to antagonize the enhancement of morphine by THC indicates that THC was acting through a cannabinoid receptor mechanism.
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PMID:The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol. 963 41

Arachidonylethanolamide (AEA), the putative endogenous ligand of the cannabinoid receptor, has been shown to be a substrate for lipoxygenase enzymes in vitro. One goal of this study was to determine whether lipoxygenase-rich cells metabolize AEA. [14C]AEA was converted by human polymorphonuclear leukocytes (PMNs) to two major metabolites that comigrated with synthetic 12(S)- and 15(S)-hydroxy-arachidonylethanolamide (HAEA). Human platelets convert [14C]AEA to 12(S)-HAEA. 12(S)-HAEA binds to both CB1 and CB2 receptors with approximately the same affinity as AEA. 12(R)-HAEA, which is not produced by PMNs, has 2-fold lower affinity for the CB1 receptor and 10-fold lower affinity for the CB2 receptor than 12(S)-HAEA. 15-HAEA has a lower affinity than AEA for both receptors, with Ki values of 738 and >1000 nM for CB1 and CB2 receptors, respectively. The addition of a hydroxyl group at C20 of AEA resulted in a ligand with the same affinity for the CB1 receptor but a 4-fold lower affinity for the CB2 receptor than AEA. 12(S)-HAEA and 15-HAEA are poor substrates for AEA amidohydrolase and do not bind to the AEA uptake carrier. In conclusion, the addition of a hydroxyl group at C12 of the arachidonate backbone of AEA does not affect binding to CB receptors but is likely to increase its half-life. The addition of hydroxyl groups at other positions affects ligand affinity for CB receptors; both the position of the hydroxyl group and the configuration of the remaining double bonds are determinants of affinity.
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PMID:Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anandamide): their affinities for cannabinoid receptors and pathways of inactivation. 965 4

Marijuana and other drugs have been suggested to act as cofactors for HIV infection. Interestingly, delta 9-THC has been shown to upregulate NF kappa B, a transcription factor utilized by HIV. Therefore, it was of interest to investigate whether cannabinoids can modulate HIV infection and replication. Initially, we tested for evidence of receptor expression by examining for receptor mRNA in various cell lines used to study HIV infection and replication. Cellular RNA was isolated from SupT, and H9, H9MN, and MT-2 cells and RT-PCR was performed. Results showed that, although all of the cell lines tested were positive for CB2 mRNA, only the MT-2 cells also expressed CBI mRNA. Since the MT-2 cells expressed both CBI and CB2 receptor mRNA, we next wanted to determine whether different cannabinoid receptor agonists such as CP-55,940, delta 9-THC, WIN-55,212-2, and WIN-55,212-3 influenced infection of these cells by cell free HIV-1MN. Infectivity assays were performed where MT-2 cells were incubated with drug and cell free virus for 90 min, the free virus washed off, and the cells incubated further, and checked for virus growth by syncytia formation. It was found that the drugs significantly increased syncytia formation when MT-2 cells were cultured in the presence of both drug and cell free HIV-1MN. In conclusion, of the cell lines tested, only the MT-2 cells were positive for both CB1 and CB2 mRNA. In addition, since syncytia formation is an indication of virus infection and cytopathicity it was concluded that cannabimimetic drugs may enhance HIV-1 infection of susceptible cells.
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PMID:Cannabinoid receptor agonists enhance syncytia formation in MT-2 cells infected with cell free HIV-1MN. 966 75

In the present work, we analyzed cannabinoid receptor mRNA expression, binding and activation of signal transduction mechanisms in the fetal rat brain or in cultures of fetal neuronal or glial cells. Cannabinoid receptor binding and mRNA expression were already measurable at GD14, but they were only located in discrete regions at GD16. Among these, the hippocampus, the cerebellum and the caudate-putamen area, three regions that contain a marked signal for both binding and mRNA in the adult brain. Significant levels of binding and, in particular, of mRNA transcripts were also detected at GD16 in the cerebral cortex, midbrain and brainstem. These structures contain relatively low levels of binding and mRNA in the adult brain, suggesting that cannabinoid receptor gene is transiently expressed in atypical areas during the fetal period. The signal for cannabinoid receptor mRNA in the hippocampus, caudate-putamen and cerebral cortex progressively increased from GD16 up to GD21. At GD18 and GD21, mRNA transcripts could be measured in discrete nuclei, such as septum nuclei, ventromedial hypothalamic nucleus and others. The cerebral cortex exhibited the highest mRNA levels at GD21, although this was not accompanied by a parallel increase in binding. An important aspect is that binding measured at these ages represent binding to functional receptors because their activation by WIN-55,212-2 increased [35S]GTPgammaS binding in the same areas. This increase was reversed by a specific antagonist, SR141716. The areas where the stimulation was more marked were the midbrain and brainstem. Using cell cultures, we have observed that cannabinoid receptor mRNA is present in cortical and hippocampal neuronal cells, but not in the glial cells. However, WIN-55,212-2 was capable of stimulating [35S]GTPgammaS binding in membrane fractions obtained from cortical glial cells and this stimulation was reversed by SR141716. This was not seen with hippocampal glial cell cultures, but occurred in hippocampal and cortical neurons. In addition, the activation of these receptors with Delta9-tetrahydrocannabinol significantly reduced forskolin-stimulated cAMP production in cortical neuronal or glial cell cultures and this effect was reversed by SR141716. In summary, we have detected cannabinoid receptor binding, mRNA expression and activation of signal transduction mechanisms in the fetal rat brain (GD14-GD21), which support the view that the system constituted by these receptors and their putative endogenous ligands might play a role in specific molecular events of the brain development. Of relevance is that binding and mRNA expression appear atypically distributed in the fetal brain as compared with the adult brain, even, that their presence in white-matter-enriched areas might presumably indicate their location in non-neuronal cells. These studies with cell cultures suggest that CB1 receptor subtype is located in neuronal cells obtained from fetal brain, although preliminary evidence is provided of the existence of another receptor subtype operative in glial cells obtained from the cerebral cortex.
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PMID:Localization of mRNA expression and activation of signal transduction mechanisms for cannabinoid receptor in rat brain during fetal development. 967 90

We used RT-PCR to measure relative differences in cannabinoid receptor (CB) mRNAs in the rat eye, comparing CB1 or CB2 transcripts to that of the normalizing reference gene beta2 microglobulin (beta2m). Significantly higher levels of CB1 mRNA levels were found in the ciliary body (0.84+/-0.05% of beta2m) than in the iris, (0.34+/-0.04% of beta2m), retina (0.07+/-0.005% of beta2m) and choroid (0.06+/-0.005% of beta2m). CB2 mRNA was undetectable. This expression pattern supports a specific role for the CB1 receptor in controlling intraocular pressure, helping to explain the antiglaucoma property of cannabinoids.
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PMID:Cannabinoid receptor CB1 mRNA is highly expressed in the rat ciliary body: implications for the antiglaucoma properties of marihuana. 968 62

The endogenous cannabinoid, anandamide (arachidonoylethanolamide), and the sleep-inducing factor, oleamide (cis-9-octadecenoamide), represent two classes of long-chain fatty acid amides with several neuronal actions and metabolic pathways in common. Here we report that these two compounds are present in human breast carcinoma EFM-19 cells and rat adrenal pheochromocytoma PC-12 cells, together with the enzyme responsible for their degradation, fatty acid amide hydrolase, and the proposed biosynthetic precursors for arachidonoylethanolamide and related acylethanolamides, the N-acyl-phosphatidylethanolamines. Lipids extracted from cells labelled with [14C]ethanolamine contained radioactive compounds with the same chromatographic behaviour as arachidonoylethanolamide and acyl-PtdEtns. The levels of these compounds were not influenced by either stimulation with ionomycin in EFM-19 cells or two-week treatment with the nerve growth factor in PC-12 cells. The chemical nature of arachidonoylethanolamide, related acylethanolamides and the corresponding acyl-PtdEtns was confirmed by gas chromatographic/mass spectrometric analyses of the purified compounds, which also showed the presence of higher levels of oleamide. The latter compound, which does not activate the central CB1 cannabinoid receptor, exhibited an anti-proliferative action on EFM-19 cells at higher concentrations than arachidonoylethanolamide (IC50 = 11.3 microM for oleamide and 2.1 microM for arachidonoylethanolamide), while at a low, inactive dose it potentiated an arachidonoylethanolamide cytostatic effect. The CB1 receptor selective antagonist SR 141716A (0.5 microM) reversed the effect of both arachidonoylethanolamide and oleamide. EFM-19 cells and PC-12 cells were found to contain a membrane-bound [14C]arachidonoylethanolamide-hydrolysing activity with pH dependency and sensitivity to inhibitors similar to those previously reported for fatty acid amide hydrolase. This enzyme was inhibited by oleamide in both intact cells and cell-free preparations. The presence of transcripts of fatty acid amide hydrolase in these cells was shown by northern blot analyses of their total RNA. The rate of [14C]arachidonoylethanolamide hydrolysis by intact cells, the kinetic parameters of arachidonoylethanolamide enzymatic hydrolysis and the amounts of the fatty acid amide hydrolase transcript, were not significantly influenced by a two-week treatment with nerve growth factor and subsequent transformation of PC-12 cells into neuron-like cells. These data show for the first time that: (a) induction by nerve growth factor of a sympathetic neuronal phenotype in PC-12 cells has no effect on arachidonoylethanolamide/oleamide metabolism, (b) arachidonoylethanolamide and oleamide are autacoid suppressors of human breast cancer cell proliferation. Moreover these data lend conclusive support to the previous hypothesis that oleamide may act as an enhancer of arachidonoylethanolamide actions through competitive inhibition of its degradation.
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PMID:Biosynthesis and degradation of bioactive fatty acid amides in human breast cancer and rat pheochromocytoma cells--implications for cell proliferation and differentiation. 968 76


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