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)

1. The present study investigated the binding characteristics of various ligands to cannabinoid CB(1) receptors in human neocortex and amygdala. In addition, the functionality of CB(1) receptors in the human neocortex was assessed by examining the effects of CB(1) receptor ligands on evoked [(3)H]-dopamine (DA) release in superfused brain slices and on synaptosomal cAMP accumulation. 2. Saturation-binding assays in human neocortical and amygdala synaptosomes using a radiolabelled cannabinoid receptor agonist ([(3)H]-CP55.940) revealed pK(d) values of 8.96 and 8.63, respectively. The numbers of binding sites (B(max)) were 3.99 and 2.67 pmol (mg protein)(-1), respectively. 3. Various cannabinoid receptor ligands inhibited [(3)H]-CP55.940 binding with rank order potencies corresponding to those of previous studies in animal tissues. 4. Electrically evoked [(3)H]-DA release from human neocortical slices was inhibited by CP55.940 (IC(50) 6.76 nm, I(max) 65%) and strongly enhanced by the cannabinoid receptor antagonist AM251. However, [(3)H]-DA release was not influenced in rat neocortex. In human tissue, the estimated endocannabinoid concentration in the biophase of the release-modulating CB(1) receptors was 1.07 nm, expressed in CP55.940 units. 5. K(+)-evoked [(3)H]-DA release in the presence of tetrodotoxin (TTX) was strongly inhibited by CP55.940 in humans, but not in rats. 6. In human tissue, CP55.940 inhibited forskolin-stimulated cAMP accumulation (IC(50) 20.89 nm, I(max) 35%). AM251 blocked this effect and per se increased forskolin-stimulated cAMP accumulation by approximately 20%. 7. In conclusion, cannabinoids modulate [(3)H]-DA release and adenylyl cyclase activity in the human neocortex. CB(1) receptors are located on dopaminergic nerve terminals and seem to be tonically activated by endocannabinoids.
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PMID:Cannabinoid CB1 receptor-mediated modulation of evoked dopamine release and of adenylyl cyclase activity in the human neocortex. 1499 2

1. Peripheral cannabinoids have been shown to suppress nociceptive neurotransmission in a number of behavioral and neurophysiological studies. It is not known, however, whether cannabinoids exert this action through direct interactions with nociceptors in the periphery and/or if other processes are involved. To gain a better understanding of the direct actions of cannabinoid-vanilloid agonists on sensory neurons, we examined the effects of these compounds on trigeminal ganglion (TG) neurons in vitro. 2. AEA (EC(50)=11.0 microM), NADA (EC(50)=857 nM) and arachidonyl-2-chloroethylamide ACEA (EC(50)=14.0 microM) each evoked calcitonin gene-related peptide (CGRP) release from TG neurons. The TRPV1 antagonists iodo-resiniferatoxin (I-RTX) and capsazepine (CPZ) each obtunded AEA-, NADA-, ACEA- and capsaicin (CAP)-evoked CGRP release with individually equivalent IC(50)'s for each of the compounds (I-RTX IC(50) range=2.6-4.0 nM; CPZ IC(50) range=523-1140 microM). 3. The pro-inflammatory mediator prostaglandin E(2) significantly increased the maximal effect of AEA-evoked CGRP release without altering the EC(50). AEA, ACEA and CAP stimulated cAMP accumulation in TG neurons in a calcium- and TRPV1-dependent fashion. Moreover, the protein kinase inhibitor staurosporine significantly inhibited AEA- and CAP-evoked CGRP release. 4. The pungency of AEA, NADA, ACEA and CAP in the rat eye-wipe assay was also assessed. Interestingly, when applied intraocularly, NADA or CAP each produced nocifensive responses, while AEA or ACEA did not. 5. Finally, the potential inhibitory effects of these cannabinoids on TG nociceptors were evaluated. Neither AEA nor ACEA decreased CAP-evoked CGRP release. Furthermore, neither of the cannabinoid receptor type 1 antagonists SR141716A nor AM251 had any impact on either basal or CAP-evoked CGRP release. AEA also did not inhibit 50 mM K(+)-evoked CGRP release and did not influence bradykinin-stimulated inositol phosphate accumulation. 6. We conclude that the major action of AEA, NADA and ACEA on TG neurons is excitatory, while, of these, only NADA is pungent. These findings are discussed in relation to our current understanding of interactions between the cannabinoid and vanilloid systems and nociceptive processing in the periphery.
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PMID:Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide, N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide. 1500 99

The cannabinoid receptor subtype 1 (CB1R) is a member of the G(i)-protein-coupled receptor family and cannabinoid signaling is largely dependent on the suppression of adenylyl cyclase-catalyzed cAMP production. In cell lines transfected with the CB1R or in native tissue preparations, treatment with cannabinoid agonists reduces both basal and forskolin-stimulated cAMP synthesis. We measured extracellular cAMP concentrations in the striatum of freely moving rats utilizing microdialysis to determine if changes in cAMP concentrations in response to CB1R agonists can be monitored in vivo. Striatal infusion of the CB1R agonist WIN55,212-2 (100 microM or 1 mM), dose-dependently decreased basal and forskolin-stimulated extracellular cAMP. These effects were reversed by co-infusion of the CB1R antagonist SR141716A (30 microM), which alone had no effect up to the highest concentration tested (300 microM). These data indicate that changes in extracellular cAMP concentrations in response to CB1R stimulation can be monitored in vivo allowing the study of cannabinoid signaling in the whole animal.
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PMID:Cannabinoids reduce cAMP levels in the striatum of freely moving rats: an in vivo microdialysis study. 1504 71

The prototypical aminoalkylindole cannabinoid WIN 55,212-2 (WIN-2) has been shown to produce antihyperalgesia through a peripheral mechanism of action. However, it is not known whether WIN-2 exerts this action directly via cannabinoid receptors located on primary afferents or if other, perhaps indirect or noncannabinoid, mechanisms are involved. To address this question, we have examined the specific actions of WIN-2 on trigeminal ganglion (TG) neurons in vitro by quantifying its ability to modulate the evoked secretion of the proinflammatory neuropeptide CGRP as well as the inflammatory mediator-induced generation of cAMP. WIN-2 evoked CGRP release from TG neurons in vitro (EC(50)=26 microm) in a concentration- and calcium-dependent manner, which was mimicked by the cannabinoid receptor-inactive enantiomer WIN 55,212-3 (WIN-3). Moreover, WIN-2-evoked CGRP release was attenuated by the nonselective cation channel blocker ruthenium red but not by the vanilloid receptor type 1 (TRPV1) antagonist capsazepine, suggesting that, unlike certain endogenous and synthetic cannabinoids, WIN-2 is not a TRPV1 agonist but rather acts at an as yet unidentified cation channel. The inhibitory effects of WIN-2 on TG neurons were also examined. WIN-2 neither inhibited capsaicin-evoked CGRP release nor did it inhibit forskolin-, isoproteranol- or prostaglandin E(2)-stimulated cAMP accumulation. On the other hand, WIN-2 significantly inhibited (EC(50)=1.7 microm) 50 mm K(+)-evoked CGRP release by approximately 70%. WIN-2 inhibition of 50 mm K(+)-evoked CGRP release was not reversed by antagonists of cannabinoid type 1 (CB1) receptor, but was mimicked in magnitude and potency (EC(50)=2.7 microm) by its cannabinoid-inactive enantiomer WIN-3. These findings indicate that WIN-2 exerts both excitatory and inhibitory effects on TG neurons, neither of which appear to be mediated by CB1, CB2 or TRPV1 receptors, but by a novel calcium-dependent mechanism. The ramifications of these results are discussed in relation to our current understanding of cannabinoid/vanilloid interactions with primary sensory neurons.
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PMID:Cannabinoid receptor-independent actions of the aminoalkylindole WIN 55,212-2 on trigeminal sensory neurons. 1515 34

Experiments were designed to determine whether cannabinoids affect salivary gland function. For this purpose, the effect of anandamide on cAMP accumulation, amylase release and Na+-K+-ATPase activity was studied in rat parotid glands. Anandamide induced a concentration-dependent increase in cAMP and led to amylase release but inhibited Na+-K+-ATPase activity. These effects were blocked by the CB1 cannabinoid receptor antagonist, AM281. The inhibition of adenylyl cyclase activity by SQ 22536 impaired amylase release and Na+-K+-ATPase inhibition. The effect of anandamide on cAMP accumulation significantly correlated with its action either on amylase release or on Na+-K+-ATPase activity. Such correlation strongly supports the view that the effect of anandamide on amylase release and Na+-K+-ATPase activity is the result of cAMP accumulation. The relative potencies of the CB1 cannabinoid receptor antagonist, AM281, to block these three functional responses were similar, supporting the view that anandamide actions in parotid glands were achieved through a single receptor subtype, the CB1. Binding studies using the selective cannabinoid CB1 receptor antagonist, [3H]SR141716A, indicated the presence of the specific binding site. It may be concluded that in parotid glands the endogenous cannabinoid anandamide, bound to the CB1 cannabinoid receptor subtype, induces cAMP accumulation which in turn leads to amylase release and Na+-K+-ATPase inhibition.
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PMID:Expression and biological effects of CB1 cannabinoid receptor in rat parotid gland. 1545 Sep 42

The role of cannabinoid receptor I (CBR-1) in the induction of decidualization was examined using decidual fibroblasts and human endometrial stromal cells as model systems. Decidual fibroblasts decidualized in vitro for 3 and 6 days in the presence of the CBR-1 agonist R(+)-WIN 55,212-2 mesylate (WIN, 0.1-10 microM) expressed less of the decidualization-specific markers prolactin, CBR-1, forkhead (FKHR), TIMP-3, laminin, endometrial bleeding associated factor (EBAF), decorin and insulin-like growth factor binding protein-1 (IGFBP-1) mRNA levels compared to control cells. The maximal decrease for each transcript was in the range of 50-99%. In contrast, cells exposed to the CBR-1 inhibitor AM-251 (1 microM) expressed about two-fold higher levels of the decidualization-specific marker gene mRNAs. The WIN-exposed cells showed a marked decrease in intracellular cAMP levels and a progressive, concentration-dependent increase in DNA fragmentation (TUNEL assay) and caspase 3 levels during decidualization compared to control cells. These studies strongly suggest that activation of CBR-1 inhibits human decidualization and stimulates apoptosis by a cAMP-dependent mechanism.
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PMID:Cannabinoid receptor I activation markedly inhibits human decidualization. 1560 30

Cannabinoids are broadly immunosuppressive, and anti-inflammatory properties have been reported for certain marijuana constituents and endogenously produced cannabinoids. The CB2 cannabinoid receptor is an established constituent of immune system cells, and we have recently established that the CB1 cannabinoid receptor is expressed in mast cells. In the present study, we sought to define a role for CB1 in mast cells and to identify the signalling pathways that may mediate the suppressive effects of CB1 ligation on mast cell activation. Our results show that CB1 and CB2 mediate diametrically opposed effects on cAMP levels in mast cells. The observed long-term stimulation of cAMP levels by the Galpha(i/o)-coupled CB1 is paradoxical, and our results indicate that it may be attributed to CB1-mediated transcriptional regulation of specific adenylate cyclase isoenzymes that exhibit superactivatable kinetics. Taken together, these results reveal the complexity in signalling of natively co-expressed cannabinoid receptors and suggest that some anti-inflammatory effects of CB1 ligands may be attributable to sustained cAMP elevation that, in turn, causes suppression of mast cell degranulation.
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PMID:Anti-inflammatory potential of CB1-mediated cAMP elevation in mast cells. 1566 19

While cannabinoid receptors activate multiple signaling pathways in the brain, it remains unclear what influence the inhibition of adenylylcyclase has on the inhibition of glutamate release. In cerebrocortical nerve terminals, the cannabinoid receptor agonist WIN55,212-2 reduced KCl-evoked glutamate release through a mechanism that restricted the rise of cytoplasmic free Ca2+, but not the changes in plasma membrane depolarization. These effects were consistent with the inhibition of Ca2+ channels. Furthermore, WIN55,212-2 reduced 4-aminopyridine (4AP) evoked glutamate release to a larger extent by modulating the behavior of both Ca2+ and K(+)-channels. The inhibition of 4AP-evoked release was associated with a decrease in cytoplasmic free Ca2+ and in plasma membrane depolarization that was reverted by the potassium channel blocker, tetraethylammonium. Interestingly, the reduction of KCl- and 4AP-evoked release by WIN55,212-2 was independent of adenylylcyclase activity and did not affect cAMP. Forskolin and the beta-adrenergic receptor increase intrasynaptosomal cAMP and promote a PKA-dependent tetrodotoxin (TTX)-sensitive increase in the spontaneous release of glutamate. These two responses were reduced by WIN55,212-2. However, the glutamate release induced by Sp-8-Br-cAMPS, which directly activated PKA without affecting cAMP, was also similarly reduced by WIN55,212-2. Hence, we conclude that the inhibition of glutamate release by WIN55,212-2 is unrelated to changes in cAMP and that the inhibition of release that a decrease in cAMP might produce is occluded by the activation of additional pathways such as the inhibition of Ca2+ channels and/or the activation of K(+)-channels that strongly depress glutamate release.
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PMID:The modulation of Ca2+ and K+ channels but not changes in cAMP signaling contribute to the inhibition of glutamate release by cannabinoid receptors in cerebrocortical nerve terminals. 1575 82

To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects, including ataxia and catalepsy. More recently, a role for selective CB2 agonists in pain modification has been demonstrated. GW405833, a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound. For the first time, we show that GW405833 selectively binds both rat and human CB2 receptors with high affinity, where it acts as a partial agonist (approximately 50% reduction of forskolin-mediated cAMP production compared to the full cannabinoid agonist, CP55,940). We also report for the first time that intraperitoneal administration of GW405833 (0.3-100 mg/kg) to rats shows linear, dose-dependent increases in plasma levels and substantial penetration into the central nervous system. In addition, GW405833 (up to 30 mg/kg) elicits potent and efficacious antihyperalgesic effects in rodent models of neuropathic, incisional and chronic inflammatory pain, the first description of this compound in these models. In contrast, analgesia, sedation and catalepsy were not observed in this dose range, but were apparent at 100 mg/kg. Additionally, GW405833 was not antihyperalgesic against chronic inflammatory pain in CB2 knockout mice. These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists, and highlight the utility of GW405833 for the investigation of CB2 physiology.
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PMID:Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. 1581 1

The neuroprotective effects of Delta(9)-tetrahydrocannabinol (THC) were examined using an in vitro model in which the AF5 CNS cell line was exposed to toxic levels of N-methyl-d-aspartate (NMDA), an agonist of the NMDA glutamate receptor. NMDA toxicity was reduced by THC, but not by the more specific cannabinoid receptor agonist, WIN55,212-2. Addition of dibutyryl cAMP (dbcAMP) to the culture medium did not alter the neuroprotective effect of THC and did not unmask a neuroprotective effect of WIN55,212-2. The cannabinoid antagonist SR141716A did not inhibit the neuroprotection induced by THC or alter the response to WIN55,212-2, even in the presence of dbcAMP, indicating that the neuroprotective effect of THC was cannabinoid receptor-independent. On the other hand, both THC and WIN55,212-2 produced cellular toxicology at higher dosages, an effect which was blocked in part by SR141716A. Capsaicin, an antioxidant and vanilloid receptor agonist, also produced a protective effect against NMDA toxicology. The protective effect of capsaicin was blocked by co-application of ruthenium red, but was not blocked by the specific vanilloid receptor antagonist capsazepine, and the transient receptor potential vanilloid type 1 (TRPV1) and ANKTM1 transcripts were not detected in AF5 cells. Thus, the neuroprotective effects of THC and capsaicin did not appear to be mediated by TRP ion channel family receptors. The antioxidant alpha-tocopherol prevented neurotoxicity in a dose-dependent manner. Therefore, THC may function as an antioxidant to increase cell survival in NMDA-induced neurotoxicity in the AF5 cell model, while higher dosages produce toxicity mediated by CB1 receptor stimulation.
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PMID:Protective effects of Delta(9)-tetrahydrocannabinol against N-methyl-d-aspartate-induced AF5 cell death. 1583 19


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