Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

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

Whole-cell patch-clamp recordings were made from substantia nigra pars reticulata (SNR) neurones in rat midbrain slices to investigate the electrophysiological effects of cannabinoids. The cannabinoid receptor agonist WIN 55212-2 (10 microM) significantly reduced intranigrally evoked and spontaneous inhibitory post-synaptic currents (IPSCs) which were mediated by GABA(A) receptors. The postsynaptic current induced by bath application of GABA was not affected by the presence of WIN 55212-2. The actions of WIN 55212-2 were not mimicked by the inactive enantiomer WIN 55212-3. WIN 55212-2 also hyperpolarized the membrane of SNR neurones in a tetrodotoxin/0-Ca2+-insensitive manner. These data suggest that cannabinoids modulate the activity of SNR neurones by presynaptic inhibition of GABA inputs. They may also exert a direct post-synaptic inhibition on these neurones.
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PMID:Presynaptic inhibition of GABAergic inputs to rat substantia nigra pars reticulata neurones by a cannabinoid agonist. 955 36

The effect of cannabinoid receptor activation and blockade on the propulsive activity in the mouse small intestine was assessed in the present study by measuring the transit of an orally administered, non-absorbable marker. The cannabinoid receptor agonist WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3[(morpholinyl)methyl]pyrrolo[1,2,3-de-1, 4benzoxazin-yl]-(1-naphthalenyl)methanone mesylate) inhibited, while the selective cannabinoid CB1 receptor antagonist SR 141716A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyraz ole-carboxamide) stimulated the marker transit. Furthermore, a per se non-effective dose of SR 141716A reversed WIN 55,212-2-induced reduction of the transit. The results of the present study suggest a role for cannabinoid CB1 receptors in the control of propulsive activity in the mouse small intestine.
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PMID:Cannabinoid modulation of intestinal propulsion in mice. 957 Apr 50

The role of nitric oxide (NO) in the development of cannabinoid tolerance was examined by using N(omega)-nitro-L-arginine methyl ester (L-NAME) as an inhibitor of NO synthase. R(+)-[2,3-Dihydro-5-methyl-3 [(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-napht halenyl)methanone mesylate (WIN 55,212-2), a cannabinoid receptor agonist, or L-NAME plus WIN 55,212-2 was acutely or chronically injected i.p. to mice and analgesia, body temperature and immobility were measured. A single injection of WIN 55,212-2 induced time- and dose-dependent analgesia, hypothermia and catalepsy. L-NAME (50 mg/kg), which per se was ineffective, administered 20 min before WIN 55,212-2 did not modify the analgesic, hypothermic and cataleptic responses to the cannabinoid. When WIN 55,212-2 was administered once a day, the animals became completely tolerant to the analgesic, hypothermic and cataleptic effects within five, seven and nine days respectively. L-NAME injected once daily 20 min before WIN 55,212-2 inhibited the development of tolerance to the hypothermic and cataleptic actions but not to the analgesic action of WIN 55,212-2. Since L-NAME given chronically by itself did not modify the analgesia, hypothermia and catalepsy induced by acute administration of WIN 55,212-2, our findings suggest L-NAME acts with some selectivity on the mechanisms involved in cannabinoid tolerance.
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PMID:A role of nitric oxide in WIN 55,212-2 tolerance in mice. 957 Apr 63

Recent reports have demonstrated that cannabinoid receptor binding decreases in several neurodegenerative diseases related to extrapyramidal function. However, there is little evidence with regard to potential changes of these receptors during senescence. The present study was designed to determine the possible existence of ageing-induced changes in cannabinoid receptor binding and gene expression in extrapyramidal areas. To this end, we analysed cannabinoid receptor binding and basal and cannabinoid receptor agonist-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate binding, by using autoradiography, and cannabinoid receptor messenger RNA levels, by using in situ hybridization, in slide-mounted brain sections obtained from young (three-month-old) and aged (>two-year-old) rats. Results were as follows. Aged rats exhibited a marked decrease in cannabinoid receptor binding in most of the basal ganglia, excepting the globus pallidus which had similar binding levels in both young and aged rats. The highest decreases were in the entopeduncular nucleus (-49.6%) and substantia nigra pars reticulata (-45.2%), whereas more moderate decreases were found in the lateral caudate putamen (-29%) and only a decremental trend in the medial caudate putamen (-13.1%). These decreases in cannabinoid receptor binding were paralleled by less marked increases in WIN 55212-2-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate binding in these structures in aged rats (% of agonist stimulation: 189% in the substantia nigra; 29.4% in the lateral caudate putamen) as compared to young rats (296% and 53.2%, respectively). Contrarily, the percentage of agonist stimulation was similar in the globus pallidus, an area where cannabinoid receptor binding did not change during ageing, of aged (205.5%) and young (215.5%) rats. In addition, aged rats also exhibited significant reductions in the cannabinoid receptor messenger RNA levels in the medial (-14.3%) and, in particular, in the lateral (-29.4%) caudate putamen, the area where the cell bodies of cannabinoid receptor-containing neurons, projecting to the substantia nigra, entopeduncular nucleus and globus pallidus, are located. In summary, the synthesis and binding levels of cannabinoid receptors markedly dropped in different structures of the extrapyramidal system of aged rats. Since these receptors, located in the basal ganglia, seem to play a role in motor control, this loss of cannabinoid receptors might be related to the motor impairment which progressively appears during senescence.
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PMID:Loss of cannabinoid receptor binding and messenger RNA levels and cannabinoid agonist-stimulated [35S]guanylyl-5'O-(thio)-triphosphate binding in the basal ganglia of aged rats. 957 96

Cannabinoid receptors are members of the superfamily of G protein-coupled receptors. Their activation has previously been shown to stimulate guanosine 5'-O-(3-[35S]thio)-triphosphate ([35S]GTP gamma S) binding in a range of brain regions using both membrane preparations and autoradiography. This study evaluates the activities of structurally diverse cannabinoid receptor ligands in the GTP gamma S binding assay, comparing the relationship between receptor binding and activation and also examining efficacy differences between compounds. Using rat cerebellar membrane preparations, the effects of GDP concentration on GTP gamma S binding and the activities of a range of cannabinoid receptor ligands, including the CB1 selective antagonist SR141716A, were investigated. GDP concentration was found to have differing effects on cannabinoid-stimulated [35S]GTP gamma S binding depending on the nature of the agonist used. The stimulation produced by high efficacy compounds, such as CP 55,940 and WIN 55212-2, was increased by raising the GDP concentration, but that of a low efficacy agonist, (-)-delta-tetrahydrocannabinol, was decreased. Of the cannabinoid compounds tested, a wide range of potencies (EC50) and levels of maximal stimulation (Emax) were observed. These ranged from CP 55,244 (Emax of 165, 148-183%, and an EC50 of 0.47, 0.22-0.96, nM) through (-)-delta-tetrahydrocannabinol, cannabinol and anandamide, which produced no concentration-dependent stimulation of [35S]GTP gamma S binding under the same conditions. SR141716A competitively antagonized all the agonists against which it was tested, providing equilibrium dissociation constants (Kd values) in the sub-nanomolar range (0.06-0.40 nM), implicating a CB1 receptor mediated response. These results provide a more detailed characterization of the cannabinoid-stimulated [35S]GTP gamma S binding assay than has previously been reported.
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PMID:Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5'-O-(3-[35S]thio)-triphosphate binding assay in rat cerebellar membranes. 958 May 97

The cannabinoid receptors, CB1 and CB2, are members of the G-protein coupled receptor family and share many of this family's structural features. A highly conserved aspartic acid residue in the second transmembrane domain of G-protein coupled receptors has been shown for many of these receptors to be functionally important for agonist binding and/or G-protein coupling. To determine whether this residue is involved in cannabinoid receptor function, we used site-directed mutagenesis of receptor cDNA followed by expression of the mutant receptor in HEK 293 cells. Aspartate 163 (in CB1) and aspartate 80 (in CB2) were substituted with either asparagine or glutamate. Stably transfected cell lines were tested for radioligand binding and inhibition of cAMP accumulation. Binding of the cannabinoid receptor agonist [3H]CP-55,940 was not affected by either mutation in either the CB1 or CB2 receptor, nor were the affinities of anandamide or (-)-delta 9-tetrahydrocannabinol. Binding of the CB1-selective receptor antagonist SR141716A also was unaltered. However, the affinity of WIN 55,212-2 was attenuated significantly in the CB1, but not the CB2, mutant receptors. Studies examining inhibition of cAMP accumulation showed reduced effects of cannabinoid agonists in the mutated receptors. Our data suggest that this aspartate residue is not generally important for ligand recognition in the cannabinoid receptors; however, it is required for communication with G proteins and signal transduction.
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PMID:Mutation of a highly conserved aspartate residue in the second transmembrane domain of the cannabinoid receptors, CB1 and CB2, disrupts G-protein coupling. 958 Jun 9

The present study was designed to test the possible existence of changes in brain cannabinoid receptors in morphine-dependent mice. To this end, we compared cannabinoid receptor binding and WIN 55,212-2-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate ([35S]GTP gamma S) binding in several brain regions of mice chronically exposed to morphine or saline. The existence of opiate dependence in morphine-injected mice was assessed by analyzing the well-known jumping behavior induced by the blockade of opioid receptors with naloxone, whereas these animals were unresponsive to the blockade of cannabinoid receptors with SR141716. The different structures analyzed exhibited similar cannabinoid receptor binding levels in morphine-dependent and control mice, with the only exception of the globus pallidus, which exhibited a very small, but statistically significant, increase. In addition, the activation of cannabinoid receptors with WIN 55,212-2 increased [35S]GTP gamma S binding in most of the structures examined. The increase was of similar magnitude in morphine-dependent and control mice, except in the substantia nigra, where morphine-dependent mice exhibited lesser [35S]GTP gamma S binding levels in basal conditions, although a significantly higher WIN 55,212-2-stimulated binding. Other structures, such as the central gray substance, where there was a poor agonist-induced stimulation in control mice, exhibited, however, higher levels of WIN 55,212-2-stimulated [35S]GTP gamma S binding in morphine-dependent mice, whereas these animals tended to exhibit a higher [35S]GTP gamma S binding levels in basal conditions, although a lesser and not statistically significant WIN 55,22-2-stimulated binding, in the deep layers of the cerebral cortex. Thus, the data support the potential existence of a specific effect of morphine in the coupling of cannabinoid receptors to GTP-binding proteins, rather than on receptor binding, although this was observed only in the substantia nigra and central gray substance.
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PMID:Autoradiographic analysis of cannabinoid receptor binding and cannabinoid agonist-stimulated [35S]GTP gamma S binding in morphine-dependent mice. 964 78

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


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