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Results for “Cannabinoid Receptor Modulators”

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At least 505 records · Page 28Linked to original sources
PubMed2005

The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously self-administered by squirrel monkeys.

Anandamide, an endogenous ligand for brain cannabinoid CB(1) receptors, produces many behavioral effects similar to those of Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Reinforcing effects of THC have been demonstrated in experimental animals, but there is only indirect evidence that endogenous cannabinoids such as anandamide participate in brain reward processes. We now show that anandamide serves as an effective reinforcer of drug-taking behavior when self-administered intravenously by squirrel monkeys. We also show that methanandamide, a synthetic long-lasting anandamide analog, similarly serves as a reinforcer of drug-taking behavior. Finally, we show that the reinforcing effects of both anandamide and methanandamide are blocked by pretreatment with the cannabinoid CB(1) receptor antagonist rimonabant (SR141716). These findings strongly suggest that release of endogenous cannabinoids is involved in brain reward processes and that activation of cannabinoid CB(1) receptors by anandamide could be part of the signaling of natural rewarding events.

Animals↗
PubMed2001

Cannabinoids inhibit the formation of new synapses between hippocampal neurons in culture.

The principal psychoactive ingredient in marijuana, Delta(9)-tetrahydrocannabinol, has been shown to inhibit adenylyl cyclase activity in vitro and can lead to impairment of memory in vivo. cAMP-induced changes in synaptic plasticity are thought to underlie memory formation. We examined the effects of cannabinoid receptor agonists on forskolin-induced formation of new synapses between rat hippocampal neurons in culture. Functional synaptic boutons were identified with FM1-43-based digital imaging. Cannabimimetic drugs prevented the recruitment of new synapses by inhibiting the formation of cAMP. The inhibition produced by Win55212-2, a synthetic cannabinoid receptor agonist, was stereoselective and was reversed by a selective CB1 receptor antagonist. Both Delta(9)-tetrahydrocannabinol and the endogenous ligand, anandamide, inhibited the formation of new synapses. Win55212-2 blocked the formation of new synapses induced by forskolin, but not those evoked by a membrane permeant cAMP analog. Thus, activation of cannabinoid receptors can modulate synaptic plasticity independent of direct effects on neurotransmitter release. Preventing the formation of new synapses may contribute to the impairment of memory produced by cannabinoids.

Animals↗
PubMed2003

Fast glucocorticoid feedback favors 'the munchies'.

In a recent paper, Tasker and colleagues show that glucocorticoids (GCs) act rapidly, probably through membrane receptors, on corticotropin-releasing factor (CRF)-synthesizing cells to release endocannabinoids. These act locally at presynaptic axons via cannabinoid CB-1 receptors to reduce excitatory glutaminergic input, and therefore induce fast feedback inhibition of CRF by GCs. Similar findings in other hypothalamic neurons suggest that this action of GCs might be common in the brain, and could, in part, explain rapid GC effects on food intake.

Appetite↗
PubMed2004

Arachidonyl ethanolamide induces apoptosis of uterine cervix cancer cells via aberrantly expressed vanilloid receptor-1.

OBJECTIVES: Delta(9)-Tetrahydrocannabinol, the active agent of Cannabis sativa, exhibits well-documented antitumor properties, but little is known about the possible effects mediated by endogenous cannabinoids on human tumors. In the present study, we analyzed the effect of arachidonyl ethanolamide (AEA) on cervical carcinoma (CxCa) cell lines. METHODS: To assess the sensitivity of CxCa cells to AEA, we selected three cell lines that were exposed to increasing doses of AEA with or without antagonists to receptors to AEA. DNA fragmentation and caspase-7 activity were used as apoptosis markers. The expression of receptors to AEA were analyzed in CxCa cell lines as well as CxCa biopsies. RESULTS: The major finding was that AEA induced apoptosis of CxCa cell lines via aberrantly expressed vanilloid receptor-1, whereas AEA binding to the classical CB1 and CB2 cannabinoid receptors mediated a protective effect. Furthermore, unexpectedly, a strong expression of the three forms of AEA receptors was observed in ex vivo CxCa biopsies. CONCLUSIONS: Overall, these data suggest that the specific targeting of VR1 by endogenous cannabinoids or synthetic molecules offers attractive opportunities for the development of novel potent anticancer drugs.

Apoptosis↗
PubMed2002

Observational analysis of feeding induced by Delta9-THC and anandamide.

Endogenous cannabinoid systems have been implicated in the physiological regulation of appetite by the ability of cannabinoid receptor agonists to induce hyperphagia. Both the exogenous cannabinoid Delta9-THC and the endocannabinoid arachidonoyl ethanolamide (anandamide) stimulate eating in rats. However, there has been no detailed analysis of the adjustments to feeding behaviour underlying this action. We used observational methods to determine the specific components of feeding affected by these compounds. Two groups (n=6) of presatiated, male, Lister hooded rats received either Delta9-THC (0, 0.5, 1.0 or 2.0 mg/kg) or anandamide (0, 1.0, 5.0 or 10.0 mg/kg sc), and their behaviour in an open field was recorded for 45 min. Behaviour (eating, drinking, rearing, grooming, sniffing, locomotion, resting/inactivity, sleeping) was continuously monitored to provide data on the latency, temporal distribution, duration and frequency of each category. Under control conditions, a minority of animals ate small quantities of lab chow, with feeding beginning only after a long latency. Both Delta9-THC and anandamide selectively stimulated feeding, with a marked reduction in latency. Apart from its rapid onset, cannabinoid-induced eating retained the normal, species-typical sequence, characteristic of untreated, free-feeding rats. Our data suggest that exogenously administered cannabinoids promote eating by increasing the incentive value of food and support a role for endocannabinoids in the regulation of the appetitive aspects of feeding motivation.

Animals↗
PubMed2002

Cannabinoid CB1 receptor as a target for chlorpyrifos oxon and other organophosphorus pesticides.

Binding of the endocannabinoid anandamide or of Delta(9)-tetrahydrocannabinol to the agonist site of the cannabinoid receptor (CB1) is commonly assayed with [3H]CP 55,940. Potent long-chain alkylfluorophosphonate inhibitors of agonist binding suggest an additional, important and closely-coupled nucleophilic site, possibly undergoing phosphorylation. We find that the CB1 receptor is also sensitive to inhibition in vitro and in vivo by several organophosphorus pesticides and analogs. Binding of [3H]CP 55,940 to mouse brain CB1 receptor in vitro is inhibited 50% by chlorpyrifos oxon at 14 nM, chlorpyrifos methyl oxon at 64 nM and paraoxon, diazoxon and dichlorvos at 1200-4200 nM. Some 15 other organophosphorus pesticides and analogs are less active in vitro. The plant defoliant tribufos inhibits CB1 in vivo, without cholinergic poisoning signs, by 50% at 50 mg/kg intraperitoneally with a recovery half-time of 3-4 days, indicating covalent derivatization. [3H-ethyl]Chlorpyrifos oxon may be suitable for radiolabeling and characterization of this proposed nucleophilic site.

Animals↗
PubMed2003

Tricyclic pyrazoles. Part 1: synthesis and biological evaluation of novel 1,4-dihydroindeno[1,2-c]pyrazol-based ligands for CB1and CB2 cannabinoid receptors.

Cannabinoids receptors, cellular elements of the endocannabinoid system, have been the focus of extensive studies because of their potential functional role in several important physiological and pathological processes. To further evaluate the properties of CB receptors, especially CB(1) and CB(2) subtypes, we have designed, using SR141716A as a benchmark, a new series of rigid 1-aryl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamides. Compounds 1 were synthesized from substituted 1-aryl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acids and requisite amines. The various analogues were assayed for binding both to the brain and peripheral cannabinoid receptors (CB(1) and CB(2)). Seven of the new compounds displayed very high in vitro CB(2) binding affinities, especially 1a, 1b, 1c, 1e, 1g, 1h and 1j which showed K(i) values of 0.34, 0.225, 0.27, 0.23, 0.385, 0.037 and 0.9 nM, respectively. Compounds 1a, 1b, 1c and 1h showed the highest selectivity for CB(2) receptor with K(i)(CB(1)) to K(i)(CB(2)) ratios of 6029, 5635, 5814 and 9810, respectively. Noticeably, 1h exhibited the highest affinity and selectivity for CB(2) receptors.

Amines↗
PubMed2006

The unfolding cannabinoid story on energy homeostasis: central or peripheral site of action?

Presentations in this symposium addressed effects and modes of action of endocannabinoids in various tissues in relation to metabolic disorders. Endocannabinoids are produced and exert their effect in various brain sites, including the mesolimbic reward circuitry and the hypothalamus. Both of these regions have direct ties to energy metabolism regulation, particularly food intake and energy expenditure. These data clearly suggest that the observed beneficial effects of CB1 (cannabinoid receptor 1) receptor antagonists on obesity may be related to the central endocannabinoid system. On the other hand, data presented on cannabinoid action in the liver and white adipose tissues clearly indicate that CB1-mediated events in affecting metabolic phenotype may occur in peripheral tissues as well. This together with the reported results from human trials on CB1 antagonists showing that the initial anorectic effect of rimonabant is diminished after the first weeks while longer lasting weight loss is achieved do indicate that peripheral action of cannabinoids are very important in body weight regulation. Should this hold true in the long run, antagonizing CB1 receptors with compound not crossing the blood-brain barrier could revolutionize pharmaceutical approaches to obesity by offering a tool that short cuts the central nervous system.

Adipose Tissue↗
PubMed2006

The role of the endocannabinoid system in the control of energy homeostasis.

The endocannabinoid system has recently emerged as an important regulator of energy homeostasis, involved in the control of both appetite and peripheral fat metabolism. We briefly review current understanding of the possible sites of action and cellular mechanisms involved in the central appetitive and peripheral metabolic effects of endocannabinoids. Studies in our laboratory, using leptin-deficient obese rodents and CB1 cannabinoid receptor (CB1)-deficient mice, have indicated that endocannabinoids acting via CB1 are involved in the hunger-induced increase in food intake and are negatively regulated by leptin in brain areas involved in appetite control, including the hypothalamus, limbic forebrain and amygdala. CB1-/- mice are lean and are resistant to diet-induced obesity (DIO) despite similar energy intake to wild-type mice with DIO, suggesting that CB1 regulation of body weight involves additional peripheral targets. Such targets appear to include both adipose tissue and the liver. CB1 expressed in adipocytes has been implicated in the control of adiponectin secretion and lipoprotein lipase activity. Recent findings indicate that both endocannabinoids and CB1 are present in the liver and are upregulated in DIO. CB1 stimulation increases de novo hepatic lipogenesis through activation of the fatty acid biosynthetic pathway. Components of this pathway are also expressed in the hypothalamus where they have been implicated in the regulation of appetite. The fatty acid biosynthetic pathway may thus represent a common molecular target for the central appetitive and peripheral metabolic effects of endocannabinoids.

Animals↗
PubMed2000

[The importance of the endogenous cannabinoid system in various neuropsychiatric disorders].

The endogenous cannabinoid system was first described in 1988. There are two specific receptors, the CB2-receptor, located in the lymphatic system (spleen, lymphocytes), and the CB1-receptor occurring predominantly in the central nervous system. The CB1-receptor shows a distinct distribution in the CNS with a very high density in the cerebellum, the basal ganglia and in the hippocampus. In 1992 endogenous ligands of the cannabinoid system were discovered for the first time (e.g. anandamide and 2-arachidonylglycerol). The physiological role of these arachidonic acid derivates is still unclear. Implications of these recent discoveries for the Gilles de la Tourette syndrome, ischaemic brain lesions, schizophrenic psychoses and opiate drug dependence are described. A dysregulation in the endogenous cannabinoid/anandamide system could possibly play an import role in the etiology of Gilles de la Tourette syndrome and schizophrenic psychoses; administration of cannabinoids affects the symptoms of the Gilles de la Tourette syndrome positively, whereas cannabinoids probably have rather negative effects in schizophrenic psychoses. In ischaemic brain lesions cannabinoids seem to have a neuroprotective effect; they appear to minimize the extent of a lesion by reduction of glutamate release. Additionally the meaning of the endogenous cannabinoid system for the development of opioid drug dependency is discussed and interactions between the endogenous opioid system and the endogenous cannabainoid system are pointed out. This is of interest since it could be shown in animal experiments that the absence of CB1 receptors reduces the positive reinforcement of opiate administration.

Animals↗
PubMed2005

[Blocking the endocannabinoid system -- weight reduction and cardiovascular risk management].

Blocking the endocannabinoid system is an option that substantially reduces cardiovascular risk beyond reducing body weight. Endocannabinoids and their receptors are expressed in the central nervous system as well as in the peripheral organs and regulate the central circuits for food uptake and peripheral metabolic circuits. Within the context of food uptake the cannabinoid receptors 1 (CB (1)-receptor) is of crucial importance. Its stimulation with Delta (9)-tetrahydrocannabiol (Delta (9)-THC) or its blockade with rimonabant are clinically relevant therapeutic means to maintain body weight. Rimonabant is the first of a new class of drugs, that interferes with the endocannabinoid system by blocking the CB (1)-Receptor. In recent clinical studies a substantial reduction of body weight and waist circumference was associated with an improvement of the cardiovascular risk profile, which was marked by increased HDL-cholesterol, serum triglycerides and improved insulin sensivity.

Cannabinoid Receptor Modulators↗
PubMed2005

The conformation, location, and dynamic properties of the endocannabinoid ligand anandamide in a membrane bilayer.

The endogenous cannabinoid ligand anandamide is biosynthesized from membrane phospholipid precursors and is believed to reach its sites of action on the CB1 and CB2 receptors through fast lateral diffusion within the cell membrane. To gain a better insight on the stereochemical features of its association with the cell membrane and its interaction with the cannabinoid receptors, we have studied its conformation, location, and dynamic properties in a dipalmitoylphosphatidylcholine multilamellar model membrane bilayer system. By exploiting the bilayer lattice as an internal three-dimensional reference grid, the conformation and location of anandamide were determined by measuring selected inter- and intramolecular distances between strategically introduced isotopic labels using the rotational echo double resonance (REDOR) NMR method. A molecular model was proposed to represent the structural features of our anandamide/lipid system and was subsequently used in calculating the multispin dephasing curves. Our results demonstrate that anandamide adopts an extended conformation within the membrane with its headgroup at the level of the phospholipid polar group and its terminal methyl group near the bilayer center. Parallel static (2)H NMR experiments further confirmed these findings and provided evidence that anandamide experiences dynamic properties similar to those of the membrane phospholipids and produces no perturbation to the bilayer. Our results are congruent with a hypothesis that anandamide approaches its binding site by laterally diffusing within one membrane leaflet in an extended conformation and interacts with a hydrophobic groove formed by helices 3 and 6 of CB1, where its terminal carbon is positioned close to a key cysteine residue in helix 6 leading to receptor activation.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2004

The endogenous cannabinoid 2-arachidonoyl glycerol as in vivo chemoattractant for dendritic cells and adjuvant for Th1 response to a soluble protein.

The decision-making mechanisms that determine the choice of the appropriate effector immune response to a microbial challenge are poorly understood. The endocannabinoid 2-arachidonoylglycerol (2-AG), injected intradermally in mice together with a soluble protein and a T helper-2 (Th2) priming Toll-like receptors (TLRs) agonist during primary immunization, shifts the memory response to the Th1 type. This effect can be shown by the enhanced hypersensitivity response and by the Th1 pattern of cytokines production that was abolished by the specific cannabinoid receptor CB2 antagonist SR 144528. 2-AG seems to operate during the innate response by increasing the number of dendritic cells (DCs) migrating to the draining lymph nodes. Expression of CB2 mRNA but not of the protein was higher in immature vs. mature DCs. Consistently, in vitro, 2-AG exerted a potent chemotactic activity on both immature and mature DCs. In conclusion, we suggest that, in vivo, the endocannabinoid 2-AG may act as chemotactic substance capable of recruiting DCs and/or their precursors during the innate immune response that, in presence of a TLR agonist, consequently instruct a Th1-shifted adaptive response. As 2-AG may be induced in tissues by various stimuli at concentrations similar to that used in our study, this evidence might be of a wide-ranging pathophysiological relevance.

Adjuvants, Immunologic↗
PubMed2005

Endocannabinoid identification in the brain: studies of breakdown lead to breakthrough, and there may be NO hope.

Endocannabinoids are a class of fatty acid derivatives defined by their ability to interact with the specific cannabinoid receptors that were originally identified as the targets of Delta9-tetrahydocannabinol (Delta9-THC), the psychoactive component of cannabis. Endocannabinoids have been implicated in a growing number of important physiological and behavioral events. A full understanding of the functions of endocannabinoids will involve knowing which ones are active, and how they are produced, during any given physical event. However, studying these small lipids in the brain presents many technical challenges. New selective pharmacological tools promise to be very useful in unraveling the complexities of endocannabinoid signaling, but parallel developments from the investigation of the cellular neurophysiology of the endocannabinoid systems highlight the difficulties remaining.

Amidohydrolases↗
PubMed2006

Endocannabinoid-mediated synaptic plasticity in the CNS.

Changes in synaptic efficacy are thought to be crucial to experience-dependent modifications of neural function. The diversity of mechanisms underlying these changes is far greater than previously expected. In the last five years, a new class of use-dependent synaptic plasticity that requires retrograde signaling by endocannabinoids (eCB) and presynaptic CB1 receptor activation has been identified in several brain structures. eCB-mediated plasticity encompasses many forms of transient and long-lasting synaptic depression and is found at both excitatory and inhibitory synapses. In addition, eCBs can modify the inducibility of non-eCB-mediated forms of plasticity. Thus, the eCB system is emerging as a major player in synaptic plasticity. Given the wide distribution of CB1 receptors in the CNS, the list of brain structures and synapses expressing eCB-mediated plasticity is likely to expand.

Animals↗