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Results for “Cannabinoid Receptor Modulators”

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At least 757 records · Page 42Linked to original sources
PubMed2001

R(+)-methanandamide induces cyclooxygenase-2 expression in human neuroglioma cells via a non-cannabinoid receptor-mediated mechanism.

Cannabinoids affect prostaglandin (PG) formation in the central nervous system through as yet unidentified mechanisms. Using H4 human neuroglioma cells, the present study investigates the effect of R(+)-methanandamide (metabolically stable analogue of the endocannabinoid anandamide) on the expression of the cyclooxygenase-2 (COX-2) enzyme. Incubation of cells with R(+)-methanandamide was accompanied by concentration-dependent increases in COX-2 mRNA, COX-2 protein, and COX-2-dependent PGE(2) synthesis. Moreover, treatment of cells with R(+)-methanandamide in the presence of interleukin-1beta led to an overadditive induction of COX-2 expression. The stimulatory effect of R(+)-methanandamide on COX-2 expression was mimicked by the structurally unrelated cannabinoid Delta(9)-tetrahydrocannabinol. Stimulation of both COX-2 mRNA expression and subsequent PGE(2) synthesis by R(+)-methanandamide was not affected by the selective CB(1) receptor antagonist AM-251 or the G(i/o) protein inactivator pertussis toxin. Enhancement of COX-2 expression by R(+)-methanandamide was paralleled by time-dependent phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK. Consistent with the activation of both kinases, R(+)-methanandamide-induced COX-2 mRNA expression and PGE(2) formation were abrogated in the presence of specific inhibitors of p38 MAPK (SB203580) and p42/44 MAPK activation (PD98059). Together, our results demonstrate that R(+)-methanandamide induces COX-2 expression in human neuroglioma cells via a cannabinoid receptor-independent mechanism involving activation of the MAPK pathway. In conclusion, induction of COX-2 expression may represent a novel mechanism by which cannabinoids mediate PG-dependent effects within the central nervous system.

Analgesics, Non-Narcotic↗
PubMed2006

The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells.

Endocannabinoids are released after brain injury and believed to attenuate neuronal damage by binding to CB(1) receptors and protecting against excitotoxicity. Such excitotoxic brain lesions initially result in primary destruction of brain parenchyma, which attracts macrophages and microglia. These inflammatory cells release toxic cytokines and free radicals, resulting in secondary neuronal damage. In this study, we show that the endocannabinoid system is highly activated during CNS inflammation and that the endocannabinoid anandamide (AEA) protects neurons from inflammatory damage by CB(1/2) receptor-mediated rapid induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) in microglial cells associated with histone H3 phoshorylation of the mkp-1 gene sequence. As a result, AEA-induced rapid MKP-1 expression switches off MAPK signal transduction in microglial cells activated by stimulation of pattern recognition receptors. The release of AEA in injured CNS tissue might therefore represent a new mechanism of neuro-immune communication during CNS injury, which controls and limits immune response after primary CNS damage.

Adult↗
PubMed2005

Dopaminergic neurones: much more than dopamine?

Midbrain dopaminergic (DA) neurones sustain important physiological functions such as control of motricity, signalling of the error in prediction of rewards and modulation of emotions and cognition. Moreover, their degeneration leads to Parkinson's disease and they may be dysfunctional in other pathological states, such as schizophrenia and drug abuse. A subset of DA neurones has been known for many years to contain releasable peptides such as neurotensin and cholecystokinin. However, recent experimental evidence indicates that the phenotype of DA neurones may be much more diverse, since it is suggested that, under certain conditions, they may also release glutamate, cannabinoids and even serotonin.

Cannabinoid Receptor Modulators↗
PubMed2005

Modulation of neocortical interneurons: extrinsic influences and exercises in self-control.

Neocortical GABAergic interneurons are a highly heterogeneous cell population that forms complex functional networks and has key roles in information processing within the cerebral cortex. Mechanisms that control the output of these cells are therefore crucial in regulating excitability within the neocortex during normal and pathophysiological activities. In addition to subtype-specific modulation of GABAergic cells by neurotransmitters released by afferents from subcortical nuclei, interneurons belonging to different classes are controlled by distinct self-modulatory mechanisms, each unique and powerful. In this article, we review the diverse responses of neocortical interneurons to extrinsic and intrinsic neuromodulators. We discuss how specificity of responses might differentially influence inhibition in somatodendritic compartments of pyramidal neurons and affect the balance of activities in neocortical circuits.

Animals↗
PubMedDate not supplied

[The endocannabinoid system and the regulation of the metabolism].

The endocannabinoid system modulates many physiological functions by acting on receptors CB1 and CB2. The endocannabinoids are produced only when and where they are needed. They act locally and are immediately metabolised after their action. Overactivation of the endocannabinoid system is observed in obesity, with stimulation of the appetite in the hypothalamus and fat accumulation in the adipocytes with increase of insulin resistance and decrease of adiponectin. Nicotine use overactivates also the endocannabinoid system. CB1 blockade by a specific inhibitor (rimonabant) decreases food intake and weight in animal studies and increases adiponectin and insulin sensitivity. Moreover, rimonabant decreases tobacco dependence. Clinical studies with rimonabant are encouraging.

Cannabinoid Receptor Modulators↗
PubMed2005

Activation of large-conductance, Ca2+-activated K+ channels by cannabinoids.

We have examined the effects of the cannabinoid anandamide (AEA) and its stable analog, methanandamide (methAEA), on large-conductance, Ca2+-activated K+ (BK) channels using human embryonic kidney (HEK)-293 cells, in which the alpha-subunit of the BK channel (BK-alpha), both alpha- and beta1-subunits (BK-alphabeta1), or both alpha- and beta4-subunits (BK-alphabeta4) were heterologously expressed. In a whole cell voltage-clamp configuration, each cannabinoid activated BK-alphabeta1 within a similar concentration range. Because methAEA could potentiate BK-alpha, BK-alphabeta1, and BK-alphabeta4 with similar efficacy, the beta-subunits may not be involved at the site of action for cannabinoids. Under cell-attached patch-clamp conditions, application of methAEA to the bathing solution increased BK channel activity; however, methAEA did not alter channel activity in the excised inside-out patch mode even when ATP was present on the cytoplasmic side of the membrane. Application of methAEA to HEK-BK-alpha and HEK-BK-alphabeta1 did not change intracellular Ca2+ concentration. Moreover, methAEA-induced potentiation of BK channel currents was not affected by pretreatment with a CB1 antagonist (AM251), modulators of G proteins (cholera and pertussis toxins) or by application of a selective CB2 agonist (JWH133). Inhibitors of CaM, PKG, and MAPKs (W7, KT5823, and PD-98059) did not affect the potentiation. Application of methAEA to mouse aortic myocytes significantly increased BK channel currents. This study provides the first direct evidence that unknown factors in the cytoplasm mediate the ability of endogenous cannabinoids to activate BK channel currents. Cannabinoids may be hyperpolarizing factors in cells, such as arterial myocytes, in which BK channels are highly expressed.

Animals↗
PubMed2006

Frequency-specific and D2 receptor-mediated inhibition of glutamate release by retrograde endocannabinoid signaling.

The mechanisms underlying modulation of corticostriatal synaptic transmission by D2-like receptors (D2Rs) have been controversial. A recent study suggested that D2Rs inhibit glutamate release at this synapse, but only during high-frequency synaptic activation. Because the release of postsynaptic endocannabinoids (eCBs), which act as retrograde messengers to inhibit presynaptic glutamate release, can be triggered by D2R activation and intense synaptic activation, such a mechanism could mediate dopaminergic modulation of corticostriatal transmission. Here, we show that D2R activation reduces excitatory transmission onto striatal medium spiny neurons at a stimulation frequency of 20 Hz but not at 1 Hz. This form of inhibition requires CB1 receptor activation, as evidenced by the fact that it is blocked by AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], a CB1 antagonist, and is absent in CB1 knockout mice. It is also blocked by postsynaptic intracellular calcium chelation, by group I metabotropic glutamate receptor antagonism, and by inhibition of postsynaptic phospholipase C. These results demonstrate a previously unrecognized role for retrograde eCB signaling in reversible and frequency-specific inhibition of glutamate release by the activation of striatal D2Rs.

Animals↗
PubMed2004

The sleep lipid oleamide may represent an endogenous anticonvulsant: an in vitro comparative study in the 4-aminopyridine rat brain-slice model.

cis-Oleamide (cOA) is a putative endocannabinoid, which modulates GABA(A) receptors, Na+ channels and gap-junctions (important targets for clinical and experimental anticonvulsants). Here we address the hypothesis that cOA possesses seizure limiting properties and might represent an endogenous anticonvulsant. Field potentials were recorded from the rat hippocampus and visual cortex. The effects of cOA, were compared to carbamazepine (CBZ), pentobarbital (PB) and carbenoxolone (CRX) on 4-Aminopyridine(4AP)-induced epileptiform discharges. CBZ (100 microM), PB (50 microM) and CRX (100 microM), but not cOA (64 microM), significantly attenuated the duration of the evoked epileptiform discharges in CA1. Interictal activity in CA3 was significantly depressed by CRX and cOA (irreversible by AM251), increased by CBZ and remained unaffected by PB. CBZ, PB and CRX abolished spontaneous ictal events and attenuated evoked ictal discharges in the visual cortex. cOA did not abolish spontaneous ictal events, but significantly (albeit weakly) reduced the duration of evoked ictal events. cOA and CRX, in contrast to CBZ or PB, caused a significant delay in the development of the evoked (tonic phase) epileptiform discharges. The weak effects of cOA seem independent of cannabinoid (CB1) receptors. Enzymatic cleavage and lack of specific antagonists for cOA confound simple interpretations of its actions in slices. Its high lipophilicity, imposing a permeability barrier, may also explain the lack of anticonvulsant activity. The effects of cOA may well be masked by release of the endogenous ligand upon ictal depolarisation as we demonstrate here for established endocannabinoids. cOA does not possess profound antiepileptic actions in our hands compared to CBZ, PB or CRX.

4-Aminopyridine↗
PubMed2005

Endocannabinoid system and opioid addiction: behavioural aspects.

Cannabinoids produce a variety of pharmacological effects very similar to those elicited by opioids. Direct and indirect interactions with opioid system have been proposed to explain some cannabinoid effects such as analgesia and attenuation of opioid-withdrawal syndrome, and evidence has been provided in support to the notion that rewarding properties of cannabinoids and opioids might be functionally linked. In particular, a growing body of studies points to an important role of the endogenous cannabinoid system in the modulation of opioid rewarding and addictive effects. The current review examines progresses in the past few years in the elucidation of cannabinoid-opioid interactions in drug abuse and dependence, focusing on recent findings from behavioural studies using different animal models of addiction. Specifically, here we review data on the behavioural aspects (i.e., drug abuse, dependence, tolerance, sensitization, relapse and drug vulnerability) of the specific, often reciprocal, cross-talk between cannabinoids and opioids with particular reference to the role of the endocannabinoid system in opioid addiction. The potential biochemical mechanisms involved in these pharmacological interactions are discussed together with possible therapeutic implications in the pharmacotherapy of opioid dependence. However, individuation of the precise anatomical substrates and molecular mechanisms of such interaction still remains a complex and challenging field for future research.

Animals↗
PubMed2004

Overlapping and interactive pathways regulating appetite and craving.

Multidisciplinary research in recent years has delineated the hypothalamic hardcore wiring that encodes appetitive drive. The appetite regulating network (ARN) consisting of distinct orexigenic and anorexigenic circuitries operates in the arcuate nucleus-paraventricular nucleus axis of the hypothalamus to propagate and relay the appetitive drive, and is subject to modulation by excitatory and inhibitory messages from the lateral hypothalamus and ventromedial nucleus, respectively. Reciprocal afferent humoral signals, comprised of anorexigenic leptin from white adipose tissue and orexigenic ghrelin from stomach, to the ARN integrate the moment-to-moment regulation of energy homeostasis. Various loci in the ARN and afferent hormonal feedback circuitry in the rodent brain are important for food craving elicited by drugs of abuse. This convergence of neurochemical and hormonal signaling has now paved the way to address the fundamental question of whether cellular and molecular events that underlie the appetitive drive in response to diminished energy stores in the body are akin to drug craving during withdrawal in humans.

Adipose Tissue↗
PubMed2003

Antioxidant properties of the vasoactive endocannabinoid, 2-arachidonoyl glycerol (2-AG).

Reactive oxygen species (ROS) were shown to play a role in altering blood-brain barrier (BBB) permeability and formation of brain edema induced by trauma and/or ischemia. 2-arachidonoyl glycerol (2-AG), a novel, potent vasodilatory and cytoprotective endocannabinoid has been implicated to act as an antioxidative agent. This study examines: 1) the possible 2-AG modulation of BBB injury and edema formation induced by closed head injury (CHI); and 2) comparable effects between 2-AG and 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TPL), a known antioxidant nitroxide on endothelial Ca2+ and cytoskeletal responses to H2O2 (ROS). 2-AG treatment reduced the CHI-induced increase in BBB permeability and brain edema. The endothelial H2O2-stimulated Ca2+ mobilization and cytoskeleton (vimentin) rearrangement was modified by either 2-AG or TPL. These findings provide evidence of 2-AG antioxidant activity and are consistent with the involvement of ROS in the pathomechanism of CHI-induced BBB injury and brain edema.

Animals↗
PubMed2006

Endocannabinoids in chronic migraine: CSF findings suggest a system failure.

Based on experimental evidence of the antinociceptive action of endocannabinoids and their role in the modulation of trigeminovascular system activation, we hypothesized that the endocannabinoid system may be dysfunctional in chronic migraine (CM). We examined whether the concentrations of N-arachidonoylethanolamide (anandamide, AEA), palmitoylethanolamide (PEA), and 2-arachidonoylglycerol (2-AG) in the CSF of patients with CM and with probable CM and probable analgesic-overuse headache (PCM+PAOH) are altered compared with control subjects. The above endocannabinoids were measured by high-performance liquid chromatography (HPLC), and quantified by isotope dilution gas-chromatography/mass-spectrometry. Calcitonin gene-related peptide (CGRP) levels were also determined by RIA method and the end products of nitric oxide (NO), the nitrites, by HPLC. CSF concentrations of AEA were significantly lower and those of PEA slightly but significantly higher both in patients with CM and PCM+PAOH than in nonmigraineur controls (p<0.01 and p<0.02, respectively). A negative correlation was found between AEA and CGRP levels in CM and PCM+PAOH patients (r=0.59, p<0.01 and r=-0.65, p<0.007; respectively). A similar trend was observed between this endocannabinoid and nitrite levels. Reduced levels of AEA in the CSF of CM and PCM+PAOH patients may reflect an impairment of the endocannabinoid system in these patients, which may contribute to chronic head pain and seem to be related to increased CGRP and NO production. These findings support the potential role of the cannabinoid (CB)1 receptor as a possible therapeutic target in CM.

Adult↗
PubMed2005

Endocannabinoid signaling in stress, medicine and wellness.

Based on self-care and stress research, it is reasonable to propose that our bodies contain naturally occurring properties, that is, tools that serve to maintain our health and integrity for a passable period of time, even in times of stress: These processes, including endocannabinoid autoregulation, might in part determine our well-being and life span. Such properties would also manifest themselves during times of stress, i.e, stress reduction. Stress potentially triggers endocannabinoid and NO synthesis and release. In fact, endocannabinoids exert stress-reducing functions by their potential to modulate norepinephrine release, e.g., via constitutive NO activation, therefore suggesting a sympatho-inhibitory mechanism that effectively diminishes sympathetic tone. This stress-reducing and health-promoting potential can be detected not only in central but also peripheral pathways, again indicating general or systemic down-regulation. In this process, signaling molecules such as the endocannabinoids may play a role in connecting mind and body phenomena, and one could speculate that such evolutionarily old autoregulatory pathways, by using endocannabinoids as one type of their molecular messengers and constitutive NO as a possible converging point, are involved in natural or innate health promotion, including wellness, reward and pleasure. Consequently, endocannabinoid research has now become a focus not only of neurobiological but also medical science: With this interdisciplinary approach, we will gather new insight on these fascinating molecules and their healing properties in the coming years ahead.

Animals↗
PubMed2000

Emerging physiological roles for N-acylphosphatidylethanolamine metabolism in plants: signal transduction and membrane protection.

The activation of N-acylphosphatidylethanolamine (NAPE) metabolism in plants appears to be associated mostly with cellular stresses. In response to pathogen elicitors, NAPE is hydrolzyed by phospholipase-D (PLD), and corresponding medium-chain, saturated N-acylethanolamines (NAEs) are released by plant cells where they act as lipid mediators to modulate ion flux and activate defense gene expression. In desiccated seeds of higher plants, long-chain, saturated and unsaturated NAEs are prevalent, but are rapidly metabolized during the first few hours of imbibition, a period of substantial osmotic stress. NAPE synthesis is increased in seeds during this same period of rapid rehydration. A membrane-bound enzyme designated NAPE synthase has been purified from imbibed cottonseeds and its unusual biochemical properties suggest that it may scavenge free fatty acids in vivo. This feature of NAPE metabolism may be unique to higher plants a may be a mechanism for the rapid recycling of fatty acids back into membrane-associated NAPE. Altogether, increasing evidence indicates that NAPE metabolism in plants shares functional similarities with NAPE metabolism in animal systems, including signal transduction and cellular protection. In particular, the emerging role of released NAEs as lipid mediators in plant defense signaling represents an intriguing parallel to 'endocannabinoid signaling' in several mammalian cell types.

Cannabinoid Receptor Modulators↗
PubMed2004

Delta 9-tetrahydrocannabinol antagonizes endocannabinoid modulation of synaptic transmission between hippocampal neurons in culture.

Cannabinoids inhibit excitatory synaptic transmission between hippocampal neurons in culture. Delta9-tetrahydrocannabinol (THC), the principal psychoactive component in marijuana, acts as a partial agonist at these synapses. Thus, THC inhibited but did not block synaptic transmission when applied alone and, when applied in combination with WIN552212-2, it partially reversed the effects of this full agonist. Here, we address the question of how THC might interact with endocannabinoid signaling. Reducing the extracellular Mg2+ concentration to 0.1 mM elicited a repetitive pattern of glutamatergic synaptic activity that produced intracellular Ca2+ concentration spikes that were measured by indo-1-based microfluorimetry. The endocannabinoid, 2-arachidonyl glycerol (2-AG) produced a concentration-dependent and complete inhibition of spike frequency with an EC50 of 63 +/- 13 nM. 2-AG (1 microM) inhibition of spiking was blocked by SR141716A (1 microM). THC (100 nM) antagonized the actions of 2-AG producing a parallel shift in the concentration-response relationship for 2-AG (EC50 of 1430 +/- 254 nM). The attenuation of 2-AG (1 microM) inhibition of synaptic activity by THC was concentration-dependent with an IC50 of 42 +/- 9 nM. These results demonstrate that THC can antagonize endocannabinoid signaling. Thus, the effects of THC on synaptic transmission are predicted to depend on the level of endocannabinoid tone.

Animals↗
PubMed2003

Discovering potent and selective reversible inhibitors of enzymes in complex proteomes.

To realize the promise of genomics-based therapeutics, new methods are needed to accelerate the discovery of small molecules that selectively modulate protein activity. Toward this end, advances in combinatorial synthesis have provided unprecedented access to large compound libraries of considerable structural complexity and diversity, shifting the bottleneck in drug discovery to the development of efficient screens for protein targets. Screening for reversible enzyme inhibitors typically requires extensive target-specific work, including protein expression and purification, as well as the development of specific substrate assays. Here we report a proteomic method for the discovery of reversible enzyme inhibitors that avoids these steps. We show that competitive profiling of a library of candidate serine hydrolase inhibitors in complex proteomes with activity-based chemical probes identifies nanomolar reversible inhibitors of several enzymes simultaneously, including the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH), triacylglycerol hydrolase (TGH) and an uncharacterized membrane-associated hydrolase that lacks known substrates. The strategy tests inhibitors against numerous enzymes in parallel, assigning both potency and selectivity factors to each agent. In this way, promiscuous inhibitors were readily rejected in favor of equally potent compounds with 500-fold or greater selectivity for their targets.

Amidohydrolases↗
PubMed2005

Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis.

Theiler's virus infection of the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). Cannabinoids have been shown to exert beneficial effects on animal models of MS and evidence suggests that the endocannabinoid system plays a role in the tonic control of spasticity. In this study we show that OMDM1 [(R)-N-oleoyl-(1'-hydroxybenzyl)-2'-ethanolamine] and OMDM2 [(S)-N-oleoyl-(1'-hydroxybenzyl)-2'-ethanolamine], two selective inhibitors of the putative endocannabinoid transporter and hence of endocannabinoid inactivation, provide an effective therapy for Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Treatment of TMEV-infected mice with OMDM1 and OMDM2 enhanced anandamide levels in the spinal cord and ameliorated motor symptoms. This was associated with a down-regulation of inflammatory responses in the spinal cord. In addition we show that OMDM1 and OMDM2 down-regulate macrophage function by (i) decreasing the surface expression of major histocompatibility complex (MHC) class II molecules, (ii) inhibiting nitric oxide synthase-2 (NOS-2) expression and (iii) reducing the production of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and interleukin-12 (IL-12p40). Taken together, these results point to the manipulation of the endocannabinoid system as a possible strategy to develop future MS therapeutic drugs.

Animals↗
PubMed2000

Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice.

This investigation reports the possible role of the endocannabinoid anandamide on modulating the behavioral and neurochemical consequences of semi-starvation. We studied the effect of very low dose anandamide (0.001 mg/kg) administration on food intake, cognitive function and catecholaminergic and serotonergic pathways in two murine brain areas concerned with appetite (hypothalamus) and learning (hippocampus), and the peripheral corticosterone response to the stress of 40% diet restriction. Anandamide-treated mice consumed 44% more food (P<0.05) during 1 week of 2.5-h feeding each day. In the hypothalamus, there were significantly increased concentrations of norepinephrine (P<0.01), dopamine (P<0.05) and 5-hydroxytryptamine (5-HT) (P<0.001). In the hippocampus, anandamide increased significantly norepinephrine and dopamine, but decreased 5-HT (all at P<0.001). Diet restriction was accompanied in both areas by a significant decrease in all neurotransmitter concentrations that were partially restored by anandamide for dopamine and 5-HT, but not for norepinephrine. In animals on diet restriction, anandamide significantly improved impaired maze performance. Norepinephrine turnover and plasma corticosterone levels were also raised significantly by anandamide. The fact that low dose anandamide improved food intake, cognitive function and reversed some of the neurotransmitter changes caused by diet restriction, might have implications for the treatment of cachexia associated with acquired immunodeficiency syndrome (AIDS) and cancer, for mood changes sometimes associated with dieting, and in the extreme case, of patients with anorexia.

Animals↗