UNIPROT:P21554 - FACTA Search

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)

This study provides the first demonstration that central cannabinoids modulate the antinociceptive actions of metabotropic glutamate receptors (mGluRs) on formalin-induced temporomandibular joint (TMJ) nociception. Noxious scratching behavior induced by formalin injection in the TMJ was used as a model of pain. Intracisternal injection of 30mug of WIN 55,212-2, a non-subtype selective cannabinoid receptor agonist, attenuated the number of scratches by 75% as compared with the vehicle-treated group, whereas vehicle alone or 3 or 10 microg of WIN 55,212-2 had no effect. To explore the postulated interaction between central cannabinoid receptors and mGluRs, effects of combined administration of sub-analgesic doses of WIN 55,212-2 and group II or III mGluR agonists were tested. Group II or III mGluRs agonists were administered intracisternally 10 min after intracisternal administration of WIN 55,212-2. Neither 100 nmol APDC, a group II mGluRs agonist, nor L-AP4, a group III mGluR agonist, altered nociceptive behavior when given alone but significantly inhibited the formalin-induced nociceptive behavior in the presence of a sub-threshold dose ( 3microg) of WIN 55,212-2. The ED50 value of APDC or L-AP4 was significantly reduced upon co-treatment with WIN 55,212-2 than in the vehicle-treated group, highlighting the important therapeutic potential of the combined administration of group II or III mGluR agonists with cannabinoids to effectively treat inflammatory pain associated with the TMJ. Potentiating effects of group II or III mGluRs agonists will likely permit the administration of cannabinoids at doses that do not achieve significant accumulation to produce undesirable motor dysfunction.
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PMID:Low doses of cannabinoids enhance the antinociceptive effects of intracisternally administered mGluRs groups II and III agonists in formalin-induced TMJ nociception in rats. 1856 58

The hypokinetic profile of certain cannabinoid agonists becomes these compounds as promising medicines to attenuate the hyperkinesia that characterizes the first grades of Huntington's disease (HD) and that represents the major neurological abnormality in this disease. The fact that CB(1) receptors, the receptor type involved in motor effects of cannabinoid agonists, are significantly reduced in the basal ganglia during the progression of HD represents a convincing explanation for the hyperkinesia typical of this disorder and supports the usefulness of enhancing CB(1) receptor signaling in HD. However, further studies revealed that the key property that enables certain cannabinoid agonists to reduce hyperkinesia is their capability to directly activate vanilloid TRPV(1) receptors. Cannabinoids may also serve to delay/arrest the progression of HD by protecting striatal projection neurons from death. Several cannabinoid agonists have been tested for this purpose in various animal models of HD, and these studies revealed that the major characteristics that enable cannabinoids to provide neuroprotection are three: (i) a reduction in inflammatory events exerted through activating CB(2) receptors located in glial cells; (ii) a normalization of glutamate homeostasis, then limiting excitotoxicity, an effect that would be exerted through CB(1) receptors; and (iii) an antioxidant effect exerted by cannabinoid receptor-independent mechanisms. The changes experienced by the endocannabinoid signaling system during the striatal degeneration support this neuroprotective effect, particularly the up-regulatory responses proved by CB(2) receptors in glial cells recruited at lesioned sites. The present article will review the neurochemical and pharmacological bases that sustain the importance of the endocannabinoid system in the pathophysiology of HD, trying to collect the present information and the future lines for research on the therapeutic potential of this system in this disorder.
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PMID:The endocannabinoid system in Huntington's disease. 1878 82

The endocannabinoid system is a neuromodulatory system which controls the release of multiple neurotransmitters, including glutamate and both, the endocannabinoid and glutamatergic systems, have been implicated in alcohol relapse. Cannabinoid agonists induce an increase in relapse-like drinking whereas glutamate receptor antagonists could prevent it. Here we hypothesize that cannabinoid-induced increases in relapse-like alcohol drinking could be mediated by glutamatergic N-methyl-d-aspartate (NMDA) receptors. To test this hypothesis, Wistar rats with a background of alcohol operant self-administration were treated with the cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl), pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55.212-2, WIN) (2.0 mg/kg) during periods of alcohol deprivation. For five consecutive days, 30 min before the reintroduction of alcohol, rats were injected with the NMDA/glycine receptor antagonist 7-chloro-4-hydroxy-3-(3-phenoxy)phenylquinolin-2-[1H]-one (L-701) (1.25-5.0 mg/kg) and alcohol reinforcement was evaluated. Our results clearly show that L-701 prevented the cannabinoid-induced increase in relapse-like drinking in a dose-dependent manner, whereas L-701 alone, in the absence of WIN treatment, did not significantly alter alcohol intake. The potentiation of relapse-like drinking induced by WIN is not caused by nonspecific anxiogenic effects, since no effect was observed in the elevated-plus maze test. These alcohol-related behaviors are linked to differential changes in CNR1 and NR1 subunit mRNA transcripts. In WIN-treated rats, an increase in CNR1 transcript levels was observed in the hypothalamus and striatum, whereas in the amygdala and anterior cingulate cortex, brain regions involved in emotional processing, a decrease was observed. Interestingly, such changes were blocked after L-701 treatment. Finally, WIN treatment also caused a reduction in NR1 mRNA levels in the amygdala. In conclusion, pharmacological inactivation of the glycine-binding site of NMDA receptors may control cannabinoid-induced relapse-like drinking, which is associated with altered expression of CNR1 and NR1 gene expression as observed after WIN treatment.
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PMID:Cannabinoid-induced increase in relapse-like drinking is prevented by the blockade of the glycine-binding site of N-methyl-D-aspartate receptors. 1897 15

In the cerebellum of juvenile mice or rats, endocannabinoids are shown to mediate depolarization-induced suppression of excitation (DSE) and retrograde suppression induced by activation of type 1 metabotropic glutamate receptor (mGluR1) at parallel fiber (PF) to Purkinje cell (PC) synapses. However, recent studies showed that glutamate also mediated retrograde signaling through presynaptic kainate receptors in the cerebellum of young adult mice and rats. We reexamined this possibility in C57BL/6 mice at postnatal day 20-35 (P20-P35) and in Sprague-Dawley rats at P18-P24. We found that DSE at PF-PC synapses was abolished by AM251, a cannabinoid receptor antagonist, and by tetrahydrolipstatin (THL), a blocker of diacylglycerol lipase (DGL) that produces an endocannabinoid, 2-arachidonoylglycerol (2-AG). AM251 and THL did not affect depolarization-induced Ca(2+) transients in PCs, and THL did not suppress cannabinoid sensitivity of PFs. Moreover, DSE at PF-PC synapses was absent in CB(1) knockout mice. AM251 also eliminated transient suppression of PF-PC synaptic transmission following a brief burst of PF stimulation, a phenomenon known to be mediated by mGluR1. These results suggest that DSE and mGluR1-mediated suppression in young adult PCs are mediated by endocannabinoids, and that glutamate, if any, has little contribution.
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PMID:Not glutamate but endocannabinoids mediate retrograde suppression of cerebellar parallel fiber to Purkinje cell synaptic transmission in young adult rodents. 1944 20

Cannabinoid administration suppresses pain by acting at spinal, supraspinal and peripheral levels. Intrinsic analgesic pathways also exploit endocannabinoids; however, the underlying neurobiological substrates of endocannabinoid-mediated analgesia have remained largely unknown. Compelling evidence shows that, upon exposure to a painful environmental stressor, an endocannabinoid molecule called 2-arachidonoylglycerol (2-AG) is mobilized in the lumbar spinal cord in temporal correlation with stress-induced antinociception. We therefore characterized the precise molecular architecture of 2-AG signaling and its involvement in nociception in the rodent spinal cord. Nonradioactive in situ hybridization revealed that dorsal horn neurons widely expressed the mRNA of diacylglycerol lipase-alpha (DGL-alpha), the synthesizing enzyme of 2-AG. Peroxidase-based immunocytochemistry demonstrated high levels of DGL-alpha protein and CB(1) cannabinoid receptor, a receptor for 2-AG, in the superficial dorsal horn, at the first site of modulation of the ascending pain pathway. High-resolution electron microscopy uncovered postsynaptic localization of DGL-alpha at nociceptive synapses formed by primary afferents, and revealed presynaptic positioning of CB(1) on excitatory axon terminals. Furthermore, DGL-alpha in postsynaptic elements receiving nociceptive input was colocalized with metabotropic glutamate receptor 5 (mGluR(5)), whose activation induces 2-AG biosynthesis. Finally, intrathecal activation of mGluR(5) at the lumbar level evoked endocannabinoid-mediated stress-induced analgesia through the DGL-2-AG-CB(1) pathway. Taken together, these findings suggest a key role for 2-AG-mediated retrograde suppression of nociceptive transmission at the spinal level. The striking positioning of the molecular players of 2-AG synthesis and action at nociceptive excitatory synapses suggests that pharmacological manipulation of spinal 2-AG levels may be an efficacious way to regulate pain sensation.
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PMID:Molecular architecture of endocannabinoid signaling at nociceptive synapses mediating analgesia. 1945 31

Neuronal synchronization at gamma frequency, implicated in cognition, can be evoked in hippocampal slices by pharmacological activation. We characterized spontaneous small-amplitude gamma oscillations (SgammaO) recorded in area CA3 of mouse hippocampal slices and compared it with kainate-induced gamma oscillations (KgammaO). SgammaO had a lower peak frequency, a more sinusoidal waveform and was spatially less coherent than KgammaO, irrespective of oscillation amplitude. CA3a had the smallest oscillation power, phase-led CA3c by approximately 4 ms and had the highest SgammaO frequency in isolated subslices. During SgammaO CA3c neurons fired at the rebound of inhibitory postsynaptic potentials (IPSPs) that were associated with a current source in stratum lucidum, whereas CA3a neurons often fired from spikelets, 3-4 ms earlier in the cycle, and had smaller IPSPs. Kainate induced faster/larger IPSPs that were associated with an earlier current source in stratum pyramidale. SgammaO and KgammaO power were dependent on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, gap junctions and gamma-aminobutyric acid (GABA)(A) receptors. SgammaO was suppressed by elevating extracellular KCl, blocking N-methyl-d-aspartate (NMDA) receptors or muscarinic receptors, or activating GluR5-containing kainate receptors. SgammaO was not affected by blocking metabotropic glutamate receptors or hyperpolarization-activated currents. The adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethoxyxanthine (8-CPT) and the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) increased SgammaO power, indicating that endogenous adenosine and/or endocannabinoids suppress or prevent SgammaO in vitro. SgammaO emerges from a similar basic network as KgammaO, but differs in involvement of somatically projecting interneurons and pharmacological modulation profile. These observations advocate the use of SgammaO as a natural model for hippocampal gamma oscillations, particularly during less activated behavioural states.
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PMID:Comparison between spontaneous and kainate-induced gamma oscillations in the mouse hippocampus in vitro. 1949 88

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

The aim of the present review is to summarize integrated neurochemical, morphological and neurobehavioral evidence, in particular from our laboratory, which emphasize the short- and long-term consequences of prenatal exposure to the cannabinoid receptor agonist WIN55,212-2 on rat glutamate transmission and cognitive functions. The results obtained provide evidence that maternal exposure to WIN55,212-2 induces an impairment of cognitive capacities in the offspring. This impairment is associated with alterations of cortical and hippocampal glutamate outflow, cortical neuron morphology and hippocampal long-term potentiation. These findings are in line with clinical data showing that the consumption of marijuana by women during pregnancy has negative consequences on the cognitive functions of their children. Thus, although it is difficult and sometimes misleading to extrapolate findings obtained from animal models to humans, the possibility that an alteration of glutamate transmission might underlie, at least in part, some of the cognitive deficits affecting the offspring of marijuana users, is supported.
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PMID:Short- and long-term consequences of prenatal exposure to the cannabinoid agonist WIN55,212-2 on rat glutamate transmission and cognitive functions. 1953 96

The association between cannabis use and psychosis has long been recognized. Recent advances in knowledge about cannabinoid receptor function have renewed interest in this association. Converging lines of evidence suggest that cannabinoids can produce a full range of transient schizophrenia-like positive, negative, and cognitive symptoms in some healthy individuals. Also clear is that in individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. The mechanisms by which cannabinoids produce transient psychotic symptoms, while unclear may involve dopamine, GABA, and glutamate neurotransmission. However, only a very small proportion of the general population exposed to cannabinoids develop a psychotic illness. It is likely that cannabis exposure is a "component cause" that interacts with other factors to "cause" schizophrenia or a psychotic disorder, but is neither necessary nor sufficient to do so alone. Nevertheless, in the absence of known causes of schizophrenia, the role of component causes remains important and warrants further study. Dose, duration of exposure, and the age of first exposure to cannabinoids may be important factors, and genetic factors that interact with cannabinoid exposure to moderate or amplify the risk of a psychotic disorder are beginning to be elucidated. The mechanisms by which exposure to cannabinoids increase the risk for developing a psychotic disorder are unknown. However, novel hypotheses including the role of cannabinoids on neurodevelopmental processes relevant to psychotic disorders are being studied.
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PMID:Cannabis and psychosis/schizophrenia: human studies. 1960 89

Adenosine A(2A), cannabinoid CB(1) and metabotropic glutamate 5 (mGlu(5)) receptors are all highly expressed in the striatum. The aim of the present work was to investigate whether, and by which mechanisms, the above receptors interact in the regulation of striatal synaptic transmission. By extracellular field potentials (FPs) recordings in corticostriatal slices, we demonstrated that the ability of the selective type 1 cannabinoid receptor (CB(1)R) agonist WIN55,212-2 to depress synaptic transmission was prevented by the pharmacological blockade or the genetic inactivation of A(2A)Rs. Such a permissive effect of A(2A)Rs towards CB(1)Rs does not seem to occur pre-synaptically as the ability of WIN55,212-2 to increase the R2/R1 ratio under a protocol of paired-pulse stimulation was not modified by ZM241385. Furthermore, the effects of WIN55,212-2 were reduced in slices from mice lacking post-synaptic striatal A(2A)Rs. The selective mGlu(5)R agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) potentiated the synaptic effects of WIN55,212-2, and such a potentiation was abolished by A(2A)R blockade. Unlike the synaptic effects, the ability of WIN55,212-2 to prevent NMDA-induced toxicity was not influenced by ZM241385. Altogether, these results show that the state of activation of A(2A)Rs regulates the synaptic effects of CB(1)Rs and that A(2A)Rs may control CB(1) effects also indirectly, namely through mGlu(5)Rs.
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PMID:Adenosine A2A receptors enable the synaptic effects of cannabinoid CB1 receptors in the rodent striatum. 1962 47

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