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At least 91 records · Page 5Linked to original sources

PubMed2002

The cannabinoids R(-)-7-hydroxy-delta-6-tetra-hydrocannabinol-dimethylheptyl (HU-210), 2-O-arachidonoylglycerylether (HU-310) and arachidonyl-2-chloroethylamide (ACEA) increase isoflurane provoked sleep duration by activation of cannabinoids 1 (CB1)-receptors in mice.

Cannabinoids produce antinociception via specific cannabinoid receptor activation, but there are also non-receptor mediated effects like for example the activation of the arachidonic acid cascade. Here we investigate the influence of cannabinoids (CB) on sleep duration after isoflurane anesthesia. We found that the CB receptor agonists R(-)-7-hydroxy-delta-6-tetra-hydrocannabinol-dimethylheptyl (HU-210) (0.1 mg/kg), 2-O-arachidonoylglycerylether (30 mg/kg) and arachidonyl-2-chloroethylamide (3 mg/kg) significantly prolong the duration of isoflurane induced sleep in mice (P<0.05). This effect was absent when co-injecting the selective CB(1) antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (1 mg/kg). Furthermore, HU-210 was ineffective in CB(1) receptor knockout mice (CB(1)-/-). Our behavioral tests (tail flick, rotarod) indicate that the sleep latency can be prolonged even at low drug dosages which do not influence thermal nociception. In the chosen dosages thimerosal (20 mg/kg), 2-AG (10 mg/kg), R(1)-methanandamide (R(1)-MAEA) (10 mg/kg) and flurbiprofen (27 mg/kg) were ineffective to increase sleep duration.

Anesthesia Recovery Period↗

PubMed2006

Distinct timing in the activity of cannabinoid-sensitive and cannabinoid-insensitive basket cells.

Cannabinoids are powerful modulators of inhibition, yet the precise spike timing of cannabinoid receptor (CB1R)-expressing inhibitory neurons in relation to other neurons in the circuit is poorly understood. Here we found that the spike timing of CB1R-expressing basket cells, a major target for cannabinoids in the rat hippocampus, was distinct from the other main group of basket cells, the CB1R-negative. Despite receiving the same afferent inputs, the synaptic and biophysical properties of the two cell types were tuned to detect different features of activity. CB1R-negative basket cells responded reliably and immediately to subtle and repetitive excitation. In contrast, CB1R-positive basket cells responded later and did not follow repetitive activity, but were better suited to integrate the consecutive excitation of independent afferents. This temporal separation in the activity of the two basket cell types generated distinct epochs of somatic inhibition that were differentially affected by endocannabinoids.

Animals↗

PubMed2006

Effects of castration on cannabinoid cb receptor expression and on the biological actions of cannabinoid in the parotid gland.

In the present study, we examined whether cannabinoid receptor expression and the effects of receptor stimulation vary as a function of gonadal status in a peripheral tissue, namely the male rat parotid gland. Four groups of male rats were studied: gonadal intact, castrated, castrated testosterone (1 mg/100 g bodyweight) treated and gonadal intact testosterone treated. 2. The results showed that the density of CB(1) receptors decreased after castration and that receptor density was restored to control values after testosterone treatment. This decrement was associated with a decrease of anandamide (10(-10) to 10(-5) mol/L)-induced cAMP accumulation and amylase release without changes in the anandamide-induced inhibition of Na(+)/K(+)-ATPase activity. 3. Castration did not modify either the subtype of cannabinoid receptor involved in the actions of anandamide or drug affinity for the receptor. 4. The mechanism underlying anandamide-induced cAMP accumulation, amylase release and inhibition of Na(+)/K(+)-ATPase activity, namely through the activation of adenylyl cyclase, was the same in control and castrated rats. 5. Basal cAMP accumulation, amylase release and Na(+)/K(+)-ATPase activity were not altered by castration. 6. Castration had no effect on the concentration of total protein. 7. It can be concluded that CB(1) cannabinoid receptor expression is regulated by testosterone in male rat parotid gland and this has functional implications for cAMP accumulation and amylase release.

Adenosine Triphosphatases↗

PubMed2003

The endogenous cannabinoid, anandamide, activates the hypothalamo-pituitary-adrenal axis in CB1 cannabinoid receptor knockout mice.

The purpose of this study was to investigate the effects of the endogenous cannabinoid arachidonoyl-ethanolamide, anandamide (AEA), on the activity of the hypothalamo-pituitary-adrenal (HPA) axis in cannabinoid receptor (CB(1) receptor) inactivated (KO) mice. A low dose (0.01 mg/kg i.p.) of AEA significantly increased plasma corticotropin (ACTH) and corticosterone concentrations in both wild-type (+/+) and in mutant (-/-) animals. In each case, hormone levels reached their peaks at 90 min after AEA administration. In a parallel experiment, AEA administration was preceded by the injection of SR 141716A (1.0 mg/kg), a selective and potent CB(1) receptor antagonist, or of capsazepine (5.0 mg/kg), a potent vanilloid receptor of type 1 (VR1) antagonist. The latter drugs did not prevent the effects of AEA on the HPA axis. Using Fos protein immunohistochemistry, we observed that the parvocellular part of the hypothalamic paraventricular nucleus (PVN) was activated as early as 45 min after AEA injection and reached peak levels after 60 min in both +/+ and -/- mice. Furthermore, the CB(1) and VR1 receptor antagonists did not block the effects of AEA on Fos immunoreactivity. The results strongly support the view that activation of the HPA axis produced by AEA possibly occurs via a currently unknown (CB(x)) cannabinoid receptor present in PVN.

Adrenocorticotropic Hormone↗

PubMed2003

Functional consequences of the acute administration of the cannabinoid receptor antagonist, SR141716A, in cannabinoid-naive and -tolerant animals: a quantitative 2-[14C]deoxyglucose study.

Cannabinoid systems have been shown to be involved in the regulation of ingestive behaviors. Administration of the cannabinoid antagonist, SR141716A, markedly reduces intake of sucrose solutions, food pellets, and ethanol. The purpose of the present studies was to identify the neural substrates that mediate these actions in rats using the quantitative autoradiographic 2-[14C]deoxyglucose (2-DG) method. In the first study, rats were trained to lever press in daily 15-min sessions for food pellets under a fixed-ratio schedule of food presentation. On the day of the experiment, rats received SR141716A (0, 1 or 3 mg/kg, i.p.) 15 min prior to behavioral testing, and the 2-DG procedure was initiated immediately after the operant test session. The acute administration of SR141716A dose-dependently decreased rates of responding and was accompanied by decreases in glucose utilization concentrated in the limbic system, particularly those areas mediating motivated behavior. Because the effects of SR141716A on behavior are intensified in animals tolerant to the effects of Delta(9)-THC, the purpose of the second study was to assess the effects of the SR141716A administration on food-maintained responding and rates of glucose utilization in tolerant animals. The suppression of responding was greater in tolerant than in drug-naive animals. Furthermore, decreases in cerebral metabolism were more intense and widespread. Although still concentrated in limbic regions, functional changes now included areas subserving the regulation of ingestive behavior including the hypothalamus. These data suggest that the effects of SR141716A administration shift in the tolerant animal and may involve different aspects of feeding behavior than in cannabinoid-naive animals.

Animals↗

PubMed1999

Evidence for the presence of CB1 cannabinoid receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid receptors.

The discovery of CB1 and CB2 receptors and of endogenous agonists for these receptors has sparked renewed interest in the therapeutic potential of cannabinoids. This has led to a need for strategies that will provide a better separation of wanted from unwanted effects, particularly for CB1 receptor agonists. Possible strategies are to target CB1 receptors present on neurones outside the central nervous system or novel types or subtypes of neuronal cannabinoid receptor. This paper reviews evidence for the presence of CB1 receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid receptors.

Animals↗

PubMed1999

The neurobiology of cannabinoid dependence: sex differences and potential interactions between cannabinoid and opioid systems.

Cannabis is the most widely used illicit drug in many western countries. Its psychoactive ingredient, delta9-tetrahydrocannabinol (THC), produces a variety of effects in animals and humans that are probably mediated by specific cannabinoid receptors in the brain and interactions with several neurotransmitter and neuromodulator systems. For instance, recent research has revealed an important mutual functional relationship between cannabinoids and endogenous opioid systems in mediating the pharmacological and behavioral actions produced by these agents, including their reinforcing effects. Perinatal exposure to and interactions between cannabinoids and opioids might also have long-term behavioral consequences lasting into adulthood. In this work, we present preliminary evidence examining the potential effects of maternal exposure to THC on the motivational properties of morphine in male and female adult rats, as measured by an intravenous opiate self-administration paradigm.

Animals↗

PubMed2002

Reversal of cannabinoids (delta9-THC) by the benzoflavone moiety from methanol extract of Passiflora incarnata Linneaus in mice: a possible therapy for cannabinoid addiction.

The newly reported benzoflavone moiety from the plant Passiflora incarnata Linneaus has been evaluated in light of traditional reports on the use of P. incarnata in breaking down cannabis addiction. In the modern or allopathic system of therapeutics, there has been no suitable remedy to combat the severe withdrawal effects of various cannabis products, including marihuana, marijuana, bhang, hashish, ganja, etc., the world-wide consumption of which has attained alarming proportions especially among the younger generation. Mice were given a 10-mg-kg(-1) twice-daily dose of delta9-tetrahydrocannabinol (delta9-THC) by mouth for six days to make them dependent upon cannabinoids. Concurrently, other groups of mice were administered delta9-THC along with a 10- or 20-mg-kg(-1) twice-daily dose of the benzoflavone moiety from P. incarnata orally for 6 days. Upon measuring locomotor activity during the treatment regimen, it was noticed that the mice receiving the P. incarnata extract and delta9-THC together developed significantly less tolerance and dependence, relative to the mice receiving delta9-THC alone. Upon administration of SR-141716A, a selective cannabinoid-receptor antagonist (10 mg kg(-1), p.o.) to all the groups of mice on the 7th day, an artificial withdrawal was produced due to an abrupt decline of delta9-THC levels in mouse brain. However, the typical withdrawal effects like paw tremors and head shakes were significantly less in the mice given delta9-THC+P. incarnata benzoflavone moiety for 6 days. Upon administration of 20 mg kg(-1) of the P. incarnata benzoflavone moiety to mice showing severe symptoms of withdrawal due to administration of SR-141716A, there was a marked attenuation of withdrawal effects, thereby suggesting the usefulness of the benzoflavone moiety in delta9-THC withdrawal. Thus, the benzoflavone moiety of P. incarnata, when administered concurrently with delta9-THC, prevented the development of tolerance and dependence of cannabinoids in mice. Even an acute administration of the benzoflavone moiety (20 mg kg(-1), p.o.) significantly blocked the expression of withdrawal effects in delta9-THC-dependent mice.

Administration, Oral↗

PubMed2003

Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'.

Earlier work from our laboratories has provided evidence for the existence of a subsite within the CB1 and CB2 cannabinoid receptor binding domain corresponding to substituents at the benzylic side chain position of classical cannabinoids. The existence and stereochemical features of this subsite have now been probed through the synthesis of a novel series of (-)-Delta(8)-tetrahydrocannabinol analogues bearing C1'-ring substituents. Of the compounds described here, those with C1'-dithiolane (1c), C1'-dioxolane (2d), and cyclopentyl (2a) substituents exhibited the highest affinities for CB1 and CB2. We used molecular modeling approaches to better define the stereochemical limits of the putative subsite. In vitro pharmacological testing found 1c to be a potent CB1 agonist.

Animals↗

PubMed2004

Cannabinoid CB1 receptor protein expression in the rat choroid plexus: a possible involvement of cannabinoids in the regulation of cerebrospinal fluid.

Cannabinoid CB1 receptors in the brain are expressed on axon terminals presynaptic to neurons that express fatty acid amide hydrolase (FAAH). Postsynaptic FAAH catabolizes endocannabinoids which act as short-range transmitters. It has been previously shown that FAAH is also expressed in the epithelial cells of the choroid plexus. Using immunohistochemisty, we found that CB1 receptor protein is also expressed in choroid plexus epithelia. This is consistent with the hypothesis that FAAH in choroid plexus epithelial cells catabolizes endocannabinoids close to their site of action. Cannabinoids may then act directly on choroid plexus cells, and thereby contribute to the regulation of the composition of the CSF.

Animals↗

PubMed2001

Activation of CB1 cannabinoid receptors in rat hippocampal slices inhibits potassium-evoked cholecystokinin release, a possible mechanism contributing to the spatial memory defects produced by cannabinoids.

Cannabinoid use is known to disrupt learning and memory in a number of species. cholecystokinin (CCK) release and CCK receptors have been implicated in spatial memory processes in rodents. Rat hippocampal CCK interneurons express cannabinoid 1 receptors (CB1). The CB1 agonist R(+)WIN 55,212-2 (WIN+), at 1 and 10 micromol, strongly inhibited potassium-evoked CCK release from rat hippocampal slices, while the inactive isomer S(-)WIN,55,212-3 (WIN-) had no effect. CCK release from cerebral cortical slices was not altered by WIN+.

Animals↗

PubMed2000

Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells.

We examined the effect of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, on the intracellular free Ca(2+) concentrations in HL-60 cells that express the cannabinoid CB2 receptor. We found that 2-arachidonoylglycerol induces a rapid transient increase in intracellular free Ca(2+) concentrations in HL-60 cells. The response was affected by neither cyclooxygenase inhibitors nor lipoxygenase inhibitors, suggesting that arachidonic acid metabolites are not involved. Consistent with this notion, free arachidonic acid was devoid of any agonistic activity. Importantly, the Ca(2+) transient induced by 2-arachidonoylglycerol was blocked by pretreatment of the cells with SR144528, a CB2 receptor-specific antagonist, but not with SR141716A, a CB1 receptor-specific antagonist, indicating the involvement of the CB2 receptor but not the CB1 receptor in this cellular response. G(i) or G(o) is also assumed to be involved, because pertussis toxin treatment of the cells abolished the response. We further examined the structure-activity relationship. We found that 2-arachidonoylglycerol is the most potent compound among a number of naturally occurring cannabimimetic molecules. Interestingly, anandamide and N-palmitoylethanolamine, other putative endogenous ligands, were found to be a weak partial agonist and an inactive ligand, respectively. These results strongly suggest that the CB2 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is abundant in the immune system.

Amides↗

PubMed1995

Prevention by the cannabinoid antagonist, SR141716A, of cannabinoid-mediated blockade of long-term potentiation in the rat hippocampal slice.

Incubation of rat hippocampal slices in the presence of the synthetic cannabinoid (-)-11-OH-delta 8-dimethylheptyl tetrahydrocannabinol (HU-210) (100 nM) prevented the induction of long-term potentiation (LTP). Slices co-incubated with both HU-210 (100 nM) and the cannabinoid antagonist, SR141716A (100 nM), exhibited tetanically induced LTP, comparable to control slices. Intriguingly, coincubation with HU-210 and SR141716A prevented the induction of the early, short-term phase of LTP.

Animals↗

PubMed1998

Protein kinase C disrupts cannabinoid actions by phosphorylation of the CB1 cannabinoid receptor.

We have found that phosphorylation of a G-protein-coupled receptor by protein kinase C (PKC) disrupts modulation of ion channels by the receptor. In AtT-20 cells transfected with rat cannabinoid receptor (CB1), the activation of an inwardly rectifying potassium current (Kir current) and depression of P/Q-type calcium channels by cannabinoids were prevented by stimulation of protein kinase C by 100 nM phorbol 12-myristate 13-acetate (PMA). In contrast, activation of Kir current by somatostatin was unaffected, and inhibition of calcium channels was only modestly attenuated. The possibility that PKC acted by phosphorylating CB1 receptors was confirmed by demonstrating that PKC phosphorylated a single serine (S317) of a fusion protein incorporating the third intracellular loop of CB1. Mutating this serine to alanine did not affect the ability of CB1 to modulate currents, but it eliminated disruption by PMA, demonstrating that PKC can disrupt ion channel modulation by receptor phosphorylation.

Analgesics↗

PubMed2004

Cannabinoid signaling in rat cerebellar granule cells: G-protein activation, inhibition of glutamate release and endogenous cannabinoids.

Previous studies have indicated that cannabinoids inhibit presynaptic neurotransmitter release in brain through CB1 receptors. To examine this issue in a primary neuronal culture system, rat cerebellar granule cells (CGCs) were prepared. [35S]GTPgammaS binding assays in saponin-permeabilized CGCs showed that G-protein activation by the CB1 agonist, WIN55212-2, and adenosine A1 agonist, phenylisopropyladenosine, was maximal during the second week in culture. Delta9-tetrahydrocannabinol stimulated [35S]GTPgammaS binding to a lesser degree than WIN55212-2, and the antagonists SR141716A and AM281 acted as inverse agonists in intact CGCs, but not in CGC membrane preparations. Ten micromolar WIN55212-2 and Delta9-tetrahydrocannabinol decreased depolarization-evoked efflux of [3H]-D-aspartate from CGCs by 32% and 13%, respectively. SR141716A and AM281 increased [3H]-D-aspartate release by 28%. The fatty acid amide hydrolase (FAAH) inhibitor phenylmethylsulfonyl fluoride (PMSF) and the anandamide uptake inhibitor AM404 inhibited transmitter release, implying that the antagonist effects were mediated by blockade of endocannabinoid activity. Levels of endocannabinoids (both anandamide and 2-arachidonyl glycerol [2-AG]) in extracts of the cells and cell incubation buffer were increased by PMSF pre-treatment. Depolarization with KCl significantly decreased the amount of anandamide and 2-AG in PMSF-treated CGCs. These results suggest that endogenous cannabinoids inhibit neurotransmitter release in CGCs, which may also release endocannabioids upon neural stimulation.

Animals↗

PubMed2002

Design, expression, and characterization of a synthetic human cannabinoid receptor and cannabinoid receptor/ G-protein fusion protein.

We report here the synthesis and characterization of two gene constructs designed to facilitate structure/function studies of the human neuronal cannabinoid receptor, CB1. The first gene, which we call shCB1, is a synthetic gene containing unique restriction sites spaced roughly 50-100 bases apart to facilitate rapid mutagenesis and cloning. A nine amino acid epitope tag (from the rhodopsin C-terminus) is also present in the shCB1 C-terminal tail to enable detection and purification using the monoclonal antibody 1D4. We find that that the shCB1 gene can be transiently expressed in COS cells with yield of approximately 10-15 micro g receptor per 15 cm plate and is wild type like in its ability to bind cannabinoid ligands. Our confocal microscopy studies indicate shCB1 targets to the membrane of HEK293 cells and is internalized in response to agonist. To facilitate functional studies, we also made a chimera in which the C-terminus of shCB1 was fused with the N-terminus of a G-protein alpha subunit, Galphai. The shCB1/Galphai chimera shows agonist stimulated GTPgammaS binding, and thus provides a simplified way to measure agonist induced CB1 activation. Taken together, the shCB1 and shCB1/Galphai gene constructs provide useful tools for biochemical and biophysical examinations of CB1 structure, activation and attenuation.

Amino Acid Sequence↗

PubMed2005

The synthetic cannabinoid R(+)WIN 55,212-2 inhibits the interleukin-1 signaling pathway in human astrocytes in a cannabinoid receptor-independent manner.

R(+)WIN 55,212-2 is a synthetic cannabinoid that controls disease progression in models of multiple sclerosis. This is associated with its ability to reduce migration of leukocytes into the central nervous system. Because leukocyte migration is dependent on induction of adhesion molecules and chemokines by pro-inflammatory cytokines, we examined the effects of R(+)WIN 55,212-2 on their expression. Using 1321N1 astrocytoma and A-172 glioblastoma as cell models we show that R(+)WIN 55,212-2, but not its inactive chiral form S(-)WIN 55,212-2, strongly inhibits the interleukin-1 (IL-1) induction of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and the chemokine IL-8. This inhibition is not mediated via the CB1 or CB2 cannabinoid receptors, because their selective antagonists and pertussis toxin failed to affect the inhibitory effects of R(+)WIN 55,212-2. Furthermore reverse transcription-PCR analysis did not detect the expression of either receptor in 1321N1 cells. R(+)WIN 55,212-2 was shown to inhibit adhesion molecule and chemokine expression at the level of transcription, because it strongly inhibited the IL-1 induction of ICAM-1, VCAM-1, and IL-8 mRNAs and blocked the IL-1 activation of their promoters. The NFkappaB pathway was then assessed as a lead target for R(+)WIN 55,212-2. NFkappaB was measured by expression of a transfected NFkappaB-regulated reporter gene. Using this assay, R(+)WIN 55,212-2 strongly inhibited IL-1 activation of NFkappaB. Furthermore R(+)WIN 55,212-2 inhibited the ability of overexpressed Myd88, Tak-1, and IKK-2 to induce the reporter gene suggesting that R(+)WIN 55,212-2 acts at or downstream of IKK-2 in the IL-1 pathway. However R(+)WIN 55,212-2 failed to inhibit IL-1-induced degradation of IkappaBalpha, excluding IKK-2 as a direct target. In addition electrophoretic mobility shift and chromatin immunoprecipitation assays showed that R(+)WIN 55,212-2 does not regulate the IL-1-induced nuclear translocation of NFkappaB or the ability of the latter to bind to promoters regulating expression of ICAM-1 and IL-8. These data suggest that R(+)WIN 55,212-2 blocks IL-1 signaling by inhibiting the transactivation potential of NFkappaB.

Active Transport, Cell Nucleus↗

PubMed2006

Cannabinoid receptor binding to membrane homogenates and cannabinoid-stimulated [35S]GTPgammaS binding to membrane homogenates or intact cultured cells.

Radioligand-binding assays can be used to obtain information about the binding characteristics of a ligand to its receptor or the general location of binding sites within a tissue or even provide evidence for the existence of a specific receptor. In the case of the cannabinoid receptor system, radioligand binding has been instrumental for each of these applications. While receptor binding can provide the above information, it says little about the efficacy of the ligand interacting with it. Binding assays that assess the effect of an unlabeled receptor ligand on the binding of the radiolabeled guanosine triphosphate (GTP) analog [35S]GTPgammaS provide such information and may be the most sensitive assays available for determining the relative efficacies of ligands that act through G protein-coupled receptors, like the CB1 cannabinoid receptor. Herein are described methods for radioligand binding to both brain membrane homogenates and membrane homogenates of cultured cells, as well as a recently developed protocol for assessing agonist-stimulated [35S]GTPgammaS binding to intact cultured cells.

Animals↗