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 antinociceptive effect of peripheral delta 9-tetrahydrocannabinol was examined in mice previously treated with an inactive dose of morphine. The ED50 of delta 9-tetrahydrocannabinol was significantly reduced by morphine, both in the tail-flick test (0.85 vs. 2.10 mg/kg) and in the hot-plate test (1.51 vs. 4.71 mg/kg and 0.73 vs. 2.47 mg/kg in jumping and paw-lick responses, respectively). The synergistic effect between morphine and delta 9-tetrahydrocannabinol was partially blocked by the cannabinoid receptor antagonist, SR-141,716 A [(N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichorophenyl)-4-methyl-3 -pyrazolecarboxamide, hydrochloride)], at a dose of 2 mg/kg (i.p.) as well as by the opioid receptor antagonist naloxone, at the dose of 1 mg/kg (s.c.). Such an effect was also blocked by i.t. nor-binaltorphimine (a kappa-selective opioid receptor antagonist) given at 20 micrograms/mouse as well as by beta-funaltrexamine (a mu-selective opioid receptor antagonist) at a dose of 2 nmol/mouse (i.c.v., 24 h before the test). Accordingly, the mu-opioid receptor agonist DAMGO ([D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin) potentiated the effect of delta 9-tetrahydrocannabinol. These data show that the synergism between morphine and delta 9-tetrahydrocannabinol appears to involve cannabinoid as well as mu-supraspinal and kappa-spinal opioid receptors.
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PMID:Potentiation of delta 9-tetrahydrocannabinol-induced analgesia by morphine in mice: involvement of mu- and kappa-opioid receptors. 900 6

Delta9-tetrahydrocannabinol (delta9-THC) elicits antinociception in rodents through the central CB1 cannabinoid receptor subtype. In addition. Delta9-THC stimulates the release of dynorphin-related peptides leading to kappa-opioid spinal antinociception. In this work we describe the effect of a mixture of thiorphan (a neutral endopeptidase EC3.4.24.11 inhibitor) and bestatin (an aminopeptidase inhibitor), administered i.c.v., on the antinociceptive effect of peripherally administered delta9-THC in mice. As in the case of morphine or DAMGO ([D-Ala2.N-Me-Phe4,Gly-ol]enkephalin), a mu-selective opioid receptor agonist, the mixture of enkephalin-degrading enzyme inhibitors also enhanced the antinociceptive effect of delta9-THC. This effect was blocked by the CB1 cannabinoid receptor antagonist, SR-141,716-A, as well as by naloxone. The kappa-opioid receptor antagonist nor-binaltorphimine, administered i.t., also antagonized the effect of this combination. Similar results were obtained with the mu-opioid receptor antagonist beta-funaltrexamine after i.c.v. administration. These results demonstrate the involvement of both mu-opioid supraspinal and kappa-opioid spinal receptors in the interaction of both opioid and cannabinoid systems regulating nociception in mice.
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PMID:Inhibition of opioid-degrading enzymes potentiates delta9-tetrahydrocannabinol-induced antinociception in mice. 968 Feb 46

The agonist-stimulated guanosine 5'-(gamma-[(35)S]thio)triphosphate binding assay was used to anatomically localize receptor-activated G-proteins by autoradiography in post mortem human brain. The optimal conditions for guanosine 5'-(gamma-[(35)S]thio)triphosphate binding to human brain sections were established in post mortem samples of the prefrontal cortex, hippocampus, basal ganglia, brainstem and cerebellar cortex. An excess of GDP (2mM) was required to decrease basal activity and obtain effective stimulation by specific agonists. guanosine 5'-(gamma-[(35)S]Thio)triphosphate binding was increased after stimulation with specific agonists of different G-protein-coupled receptors. They include cannabinoid (WIN55212-2), mu-opioid ([D-Ala(2),N-Me-Phe(4), Gly(5)-ol]enkephalin), serotonin-1A [(+/-)-8-hydroxy-2-(di-n-propylamino)tetralin] and serotonin-1B/1D (sumatriptan), cholinergic muscarinic receptors (carbachol) and alpha(2)-adrenoceptors (UK14304). Such stimulation reached 1458%, 440%, 188%, 219%, 61% and 339%, respectively, over the basal levels. In tissue sections, the use of the above-mentioned agonists (10(-4)M) showed patterns of anatomical distribution similar to those already described by receptor autoradiography, with high densities over the hippocampus (serotonin-1A receptors), cortex (alpha(2)-adrenoceptors) and striatum (mu-opioid receptors). The highest binding levels were reached with the cannabinoid receptor agonist in most of the analysed brain regions. Carbachol produced only moderate stimulation of those same regions. The blockage of agonist-stimulated guanosine 5'-(gamma-[(35)S]thio)triphosphate binding by selective antagonists verified that the effect was receptor mediated. This technique provides a method to identify modifications of the receptor-mediated activation of G-proteins in post mortem human brain with anatomical resolution. It also provides valuable information on the level of drug efficacy in the human species.
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PMID:Autoradiography of receptor-activated G-proteins in post mortem human brain. 1068 21

The nonpsychoactive plant cannabinoid, (-)-cannabidiol, modulates in vivo responses to Delta(9)-tetrahydrocannabinol. We have found that cannabidiol can also interact with cannabinoid CB(1) receptor agonists in the mouse vas deferens, a tissue in which prejunctional cannabinoid CB(1) receptors mediate inhibition of electrically evoked contractions by suppressing noradrenaline and/or ATP release. Cannabidiol (0.316-10 microM) attenuated the ability of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) to inhibit contractions in a concentration-related, surmountable manner with a K(B) value (120.3 nM) well below its reported cannabinoid receptor CB(1)/CB(2) K(i) values. Cannabidiol (10 microM) also antagonized (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940; K(B)=34 nM) and [D-Ala(2), NMePhe(4), Gly-ol]enkephalin (DAMGO; K(B)=5.6 microM) and attenuated contractile responses to noradrenaline, phenylephrine and methoxamine but not to beta, gamma-methyleneadenosine 5'-triphosphate. At 3.16-10 microM, it increased the amplitude of evoked contractions, probably by enhancing contractile neurotransmitter release. We conclude that cannabidiol antagonizes R-(+)-WIN55212 and CP55940 by acting at prejunctional sites that are unlikely to be cannabinoid CB(1) or CB(2) receptors.
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PMID:(-)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. 1245 May 75

The rewarding properties of the psychoactive constituents of marijuana, termed "cannabinoids," may reflect actions on synaptic transmission in the nucleus accumbens (NAc). Furthermore, long-term changes in these synapses may support the addictive process. Excitatory and inhibitory synapses are acutely inhibited by cannabinoids in the NAc, and endogenous cannabinoids (endocannabinoids) play a critical role in the expression of long-term depression (LTD) of excitatory cortical afferents in this structure. Because humans often use marijuana for prolonged periods, we examined the impact of long-term cannabinoid exposure on synaptic processes in an animal model. Electrophysiological recordings in rat brain slices containing the NAc were performed after chronic exposure to vehicle solution, Delta9-tetrahydrocannabinol (THC), or the cannabinoid agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2). Extracellular glutamatergic postsynaptic potentials and whole-cell GABAergic IPSCs were concentration-dependently inhibited by WIN55,212-2 in slices from naive or vehicle-treated animals. However, the sensitivity to WIN55,212-2 was diminished in chronic agonist-treated animals. In addition, cross-tolerance to the inhibitory effect of the mu-opioid agonist Tyr-D-Ala2, N-CH3-Phe4,Gly-ol-enkephalin was observed. Endocannabinoid-mediated LTD was initiated via electrical stimulation (5 min, 10 Hz) of glutamatergic afferents to the NAc and was completely blocked by the cannabinoid receptor antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] in vehicle-treated animals. LTD was not observed in brain slices from rats chronically treated with Delta9-THC or WIN55,212-2. These data demonstrate that long-term exposure to the active ingredient of marijuana blocks synaptic plasticity in the NAc and reduces the sensitivity of GABAergic and glutamatergic synapses to both cannabinoids and opioids.
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PMID:Functional tolerance and blockade of long-term depression at synapses in the nucleus accumbens after chronic cannabinoid exposure. 1283 2

Cadherin-related neuronal receptor (CNR) proteins are a diverse set of synaptic protocadherins, but little is known about its adhesive properties. We found that overexpressed CNR1 protein localized on the cell surface of HEK293T cells and increased the calcium-dependent cell aggregation potential. However, we could not detect the strong homophilic binding activity of CNR1 EC-Fc fusion protein in vitro. Parental HEK293T cells adhered to Arg-Gly-Asp (RGD) motif of EC1 domain of CNR1-Fc fusion protein. The fusion protein that the Asp73 of EC1 point-mutated to Glu (RGE-Fc) lost the adhesive activity. The adhesion activity of HEK293T cells to CNR1 EC-Fc fusion protein was completely blocked by inhibitors of integrins, including RGDS peptide and anti-beta1 integrin antibodies. The increased cell-aggregative property of CNR1 transfectants was also blocked by RGDS peptides. At cell-cell junctions of the CNR1 transfectants, co-localization between CNR1 and HEK293T endogenous beta1 integrin was observed. Furthermore, the spatiotemporal expression patterns of CNR and beta1 integrin nearly overlapped in the molecular layer of the developing mouse cerebellum in the main stage of synaptogenesis. These results indicate that CNR1 has a heterophilic, calcium-dependent cell adhesion activity with the beta1 integrin subfamily, and raise the possibility of CNR-beta1 integrin association in synaptogenesis.
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PMID:Cadherin-related neuronal receptor 1 (CNR1) has cell adhesion activity with beta1 integrin mediated through the RGD site of CNR1. 1502 37

Most of the pharmacological actions of cannabinoids are mediated by CB1 receptors. There is also evidence that these compounds can produce effects that are not mediated by the activation of identified cannabinoid receptors. Our data demonstrate that cannabinoids may directly affect the functioning of inhibitory glycine receptor (GlyR) channels. Here, we report that cannabinoid receptors agonist WIN 55,212-2, in a CB1 receptor independent manner, cause a significant potentiation of the amplitudes of glycine-activated currents (I(Gly)) in acutely isolated hippocampal CA3 and CA1 pyramidal neurons. The maximal potentiation by this compound was observed at the lowest concentration of glycine; with increasing concentrations of glycine, the potentiation significantly decreased. Also WIN 55,212-2 significantly accelerated the desensitization of Gly-induced chloride current and significantly decreased the rise time. The effects of WIN 55,212-2 on I(Gly) were not attenuated in the presence of CB1 receptor antagonist AM251, suggesting that CB1 receptor activation are not involved in action of cannabinoid on GlyRs. Altogether these data allow us to suggest the existence of a CB1R independent action of cannabinoids directly on glycine-activated currents, representing a novel antinociceptive mechanism of this compounds.
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PMID:[The synthetic cannabinoid analog WIN 55,212-2 potentiates the amplitudes of glycine-activated currents]. 1772 41

The CB(1) cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716) has been shown by many investigators to inhibit basal G-protein activity, i.e., to display inverse agonism at high concentrations. However, it is not clear whether this effect is cannabinoid CB(1) receptor-mediated. Using the ligand-stimulated [(35)S]guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) assay, we have found that 10 microM SR141716 slightly but significantly decreases the basal [(35)S]GTPgammaS binding in membranes of the wild-type and CB(1) receptor knockout mouse cortex, parental Chinese hamster ovary (CHO) cells, and CHO cells stably transfected with micro-opioid receptors, MOR-CHO. Accordingly, we conclude that the inverse agonism of SR141716 is CB(1) receptor-independent. Although the specific MOR agonist Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO) saturably and concentration-dependently stimulated [(35)S]GTPgammaS binding, SR141716 (10 microM) inhibited the basal by 25% and competitively inhibited DAMGO stimulation in the mouse cortex. In MOR-CHO membranes, DAMGO caused a 501 +/- 29% stimulation of the basal activity, which was inhibited to 456 +/- 22% by 10 microM SR141716. The inverse agonism of SR141716 was abolished, and DAMGO alone displayed weak, naloxone-insensitive stimulation, whereas the combination of DAMGO and SR141716 (10 microM each) resulted in a 169 +/- 22% stimulation of the basal activity (that was completely inhibited by the prototypic opioid antagonist naloxone) because of pertussis toxin (PTX) treatment to uncouple MORs from G(i)/G(o) proteins. SR141716 proved to bind directly to MORs with low affinity (IC(50) = 5.7 microM). These results suggest the emergence of novel, PTX-insensitive G-protein signaling that is blocked by naloxone when MORs are activated by the combination of DAMGO and SR141716.
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PMID:CB1 receptor-independent actions of SR141716 on G-protein signaling: coapplication with the mu-opioid agonist Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol unmasks novel, pertussis toxin-insensitive opioid signaling in mu-opioid receptor-Chinese hamster ovary cells. 1944 42

N-arachidonylglycine (NA-Gly) is an amino acid derivative of arachidonic acid. This compound is structurally related to anandamide (arachidonylethanolamine), which is considered an endogenous ligand of the cannabinoid receptor. NA-Gly is present at relatively high levels in the spinal cord, small intestine, and kidneys and at lower, but remarkable, levels in testes, lungs, and liver. The presence of varying levels in different organs suggests multiple functions in addition to the reported anti-inflammatory and pain suppression actions. Here a study on the interaction of NA-Gly with isolated mitochondria is reported. The results show that micromolar concentrations of NA-Gly cause: (i) an increase in the resting state respiration with both glutamate plus malate and succinate as substrates and (ii) a decrease in either ADP- or uncoupler-activated respiration. Whereas the stimulated resting state respiration was substantially reduced by cyclosporin A (CsA), the NA-Gly-inhibited State 3 respiration was almost unaffected. Measurements by blot analysis showed that NA-Gly caused a CsA-sensitive cytochrome c release. Under these conditions no matrix swelling could be detected. Experiments are also presented showing that NA-Gly caused a respiration-dependent large ROS production, which seems in turn to be responsible for the inhibition of electron transport activity and cytochrome c release.
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PMID:N-arachidonylglycine causes ROS production and cytochrome c release in liver mitochondria. 1950 48

Desensitization of the micro-opioid receptor (MOR) has been implicated as an important regulatory process in the development of tolerance to opiates. Monitoring the release of intracellular Ca(2+) ([Ca(2+)](i)), we reported that [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO)-induced receptor desensitization requires receptor phosphorylation and recruitment of beta-arrestins (betaArrs), while morphine-induced receptor desensitization does not. In current studies, we established that morphine-induced MOR desensitization is protein kinase C (PKC)-dependent. By using RNA interference techniques and subtype specific inhibitors, PKCepsilon was shown to be the PKC subtype activated by morphine and the subtype responsible for morphine-induced desensitization. In contrast, DAMGO did not increase PKCepsilon activity and DAMGO-induced MOR desensitization was not affected by modulating PKCepsilon activity. Among the various proteins within the receptor signaling complex, Galphai2 was phosphorylated by morphine-activated PKCepsilon. Moreover, mutating three putative PKC phosphorylation sites, Ser(44), Ser(144) and Ser(302) on Galphai2 to Ala attenuated morphine-induced, but not DAMGO-induced desensitization. In addition, pretreatment with morphine desensitized cannabinoid receptor CB1 agonist WIN 55212-2-induced [Ca(2+)](i) release, and this desensitization could be reversed by pretreating the cells with PKCepsilon inhibitor or overexpressing Galphai2 with the putative PKC phosphorylation sites mutated. Thus, depending on the agonist, activation of MOR could lead to heterologous desensitization and probable crosstalk between MOR and other Galphai-coupled receptors, such as the CB1.
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PMID:Agonist-dependent mu-opioid receptor signaling can lead to heterologous desensitization. 2004 90


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