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PubMed2005

The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines.

Endocannabinoids are involved in neuroprotection through numerous biochemical pathways. We have shown that the endocannabinoid 2-arachidonoyl glycerol (2-AG) is released in mouse brain after closed head injury (CHI), and treatment with exogenous 2-AG exerts neuroprotection via the central cannabinoid receptor CB1. This process involves inhibition of inflammatory signals that are mediated by activation of the transcription factor NF-kB. The present study was designed to examine the effect of 2-AG on the blood-brain barrier (BBB) and the possible inhibition of the early expression of proinflammatory cytokines, which are implicated in BBB disruption. We found that 2-AG decreased BBB permeability and inhibited the acute expression of the main proinflammatory cytokines: TNF-alpha, IL-1beta and IL-6. It also augmented the levels of endogenous antioxidants. We suggest that 2-AG exerts neuroprotection in part by inhibition of the early (1-4 h) inflammatory response and augmentation of the brain reducing power.

Animals↗
PubMed2005

Blood pressure regulation by endocannabinoids and their receptors.

Cannabinoids and their endogenous and synthetic analogs exert powerful hypotensive and cardiodepressor effects by complex mechanisms involving direct and indirect effects on myocardium and vasculature. On the one hand, endocannabinoids and cannabinoid receptors have been implicated in the hypotensive state associated with hemorrhagic, endotoxic and cardiogenic shock, and advanced liver cirrhosis. On the other hand, there is emerging evidence suggesting that the endocannabinergic system plays an important role in the cardiovascular regulation in hypertension. This review is aimed to discuss the in vivo hypotensive and cardiodepressant effects of cannabinoids mediated by cannabinoid and TRPV(1) receptors, and focuses on the novel therapeutical strategies offered by targeting the endocannabinoid system in the treatment of hypertension.

Animals↗
PubMed2006

Spinal modulation of calcitonin gene-related peptide by endocannabinoids in the development of opioid physical dependence.

Studies implicate endocannabinoids in the acute and chronic actions of opioid drugs, including the genesis of physical dependence. Previous evidence suggests that spinal release of calcitonin gene-related peptide (CGRP) and activation of its receptors contribute to opioid physical dependence. The release of CGRP at the spinal level is modulated by cannabinoid (CB1)-receptors. Thus, this study examined whether CB1-receptor activity mediates changes in CGRP underlying development of opioid physical dependence. Systemic morphine administration for 5-days elevated CGRP-immunoreactivity in the rat spinal dorsal horn. In situ hybridization of dorsal root ganglion (DRG) neurons revealed an increase in CGRP mRNA during initial (day 1-3) but not later phase (day 4-5) of morphine treatment. CGRP-immunoreactivity in DRG neurons, however, was increased in the later phase of morphine treatment. Naloxone challenge to morphine-treated animals precipitated an intense withdrawal syndrome that depleted CGRP-immunoreactivity and increased Fos expression in the dorsal horn. The Fos-response primarily occurred in neurons that expressed CGRP receptor component protein (RCP) suggesting CGRP activity contributes to neuronal activation during precipitated withdrawal. Spinal slices obtained from morphine-treated animals showed higher levels of CGRP release than from saline controls. Intrathecal co-administration of CB1-receptor antagonists, AM-251 or SR141716A, with daily morphine attenuated the behavioral manifestations of withdrawal. Treatment with AM-251 also reduced the depletion of CGRP, suppressed Fos-induction, and prevented the increase in capsaicin-evoked spinal CGRP release. Altogether, this study suggests that endocannabinoid activity, expressed via CB1-receptors, contributes to the induction of opioid physical dependence through spinal modulation of CGRP.

Animals↗
PubMed2006

Enhancement of endocannabinoid signalling during adolescence: Modulation of impulsivity and long-term consequences on metabolic brain parameters in early maternally deprived rats.

Pharmacological modulation of the endocannabinoid system is a novel but poorly explored field for potential therapy. Early maternal deprivation represents an animal model for specific aspects of neuropsychiatric disorders. This study explored whether a pharmacological manipulation of the endocannabinoid system at adolescence may restore altered phenotypes resulting from early maternal deprivation. Wistar male rats, maternally deprived for 24 h on postnatal day (PND) 9, were administered the fatty-acid amide hydrolase (FAAH) inhibitor URB597 (0, 0.1 or 0.5 mg/kg/day) for six days during adolescence (PND 31-43), while tested in the intolerance-to-delay task. Deprived (DEP) adolescent rats showed a trend for higher impulsivity levels and an increased locomotor response to novelty when compared to non-deprived (NDEP) controls. The low dose of URB597 effectively decreased impulsive behaviour specifically in DEP subjects. Moreover, long-term metabolic brain changes, induced by drug treatment during adolescence, were detected in DEP animals using proton magnetic resonance spectroscopy ((1)H MRS). Significant changes were only found within the hippocampus: N-acetyl-aspartate and total creatine were up-regulated by the low dose; glutamate and glutamate plus glutamine were conversely down-regulated by the higher dose. In summary, administration of URB597 during adolescence increased self-control behaviour and produced enduring brain biochemical modifications, in a model for neuropsychiatric disorders.

Amidohydrolases↗
PubMed2006

Changes in endocannabinoid and palmitoylethanolamide levels in eye tissues of patients with diabetic retinopathy and age-related macular degeneration.

Cannabinoid receptors and the endocannabinoids (anandamide (N-arachidonoylethanolamine--AEA) and 2-arachidonoylglycerol (2-AG)), as well as the AEA congener, palmitoylethanolamide (PEA), are involved in ocular physiology. We measured endocannabinoid and PEA levels by isotope-dilution liquid chromatography-mass spectrometric analysis in post-mortem eye tissues of patients with diabetic retinopathy (DR) or age-related macular degeneration (AMD). In eyes with DR, significantly enhanced levels of AEA were found in the retina ( approximately 1.8-fold), ciliary body ( approximately 1.5-fold) and, to a lesser extent, cornea ( approximately 1.3-fold). Surprisingly, 2-AG levels were significantly higher ( approximately 3-fold) only in the iris, whereas PEA levels only slightly increased ( approximately 1.3-fold) in the ciliary body. In eyes with AMD, significantly enhanced levels of AEA were found in the choroid ( approximately 1.3-fold), ciliary body ( approximately 1.4-fold) and cornea ( approximately 1.4-fold), whereas in the retina only a trend towards an increase ( approximately 1.5-fold) was observed. The tissue- and disease-selective nature of the changes observed suggests that the compounds analyzed here may play different roles in the control of eye function under different pathological conditions.

Amides↗
PubMed2006

A brief history of cannabinoid and endocannabinoid pharmacology as inspired by the work of British scientists.

British scientists have played a leading role in the long history of cannabinoid and endocannabinoid research. Such research has progressed from the first crucial evaluation of the medicinal properties of Cannabis sativa in the Western world to pioneering studies of the chemical constituents of this plant, the development of in vitro biological assays to study cannabinoids, the identification of the mechanism of action of cannabinoids, the discovery of endocannabinoids and the assessment of their therapeutic implications. Stemming from the many innovative ideas and achievements of these researchers, I provide a personal view of where these studies have led us thus far and where they are likely to take us in the future.

Animals↗
PubMed2002

Endocannabinoids are implicated in the infarct size-reducing effect conferred by heat stress preconditioning in isolated rat hearts.

OBJECTIVE: We have investigated the involvement of the endocannabinoid system in the delayed cardioprotection conferred by heat stress preconditioning in the isolated rat heart. METHODS: Rats were divided into eight groups (n=7 in each group), subjected to either heat stress (42 degrees C for 15 min, HS groups) or sham anaesthesia (Sham groups). Twenty-four hours later, their hearts were isolated, retrogradely perfused, and subjected to a 30-min occlusion of the left coronary artery followed by 120 min of reperfusion. Some hearts were perfused with either SR 141716 (a cannabinoid CB(1) receptor antagonist, 1 microM), SR 144528 (a CB(2) receptor antagonist, 1 microM) or L-NAME (a NOS inhibitor, 3 microM) 5 min before ischaemia and during the ischaemic period. RESULTS: The infarct size-reducing effect conferred by heat stress (35.7+/-1.8% in Sham to 14.1+/-0.6% in HS groups) was not altered by the perfusion of SR 141716 (11.2+/-1.5%) but was abolished by both SR 144528 (36.6+/-1.6%) and L-NAME (32.0+/-4.4%). In hearts from non-heat-stressed rats, perfusion with SR 141716 (32.8+/-1.6%), SR 144528 (33.4+/-2.2%) and L-NAME (31.6+/-2.9%) had no effect on infarct size. CONCLUSION: These results suggest an involvement of endocannabinoids, acting through CB(2) receptors, and NO in the cardioprotection conferred by heat stress against myocardial ischaemia. The possible interaction between both mediators of the heat stress response remains to be determined.

Analysis of Variance↗
PubMed2000

Conformational requirements for endocannabinoid interaction with the cannabinoid receptors, the anandamide transporter and fatty acid amidohydrolase.

Anandamide (N-arachidonoylethanolamine) has been identified as an endogenous ligand of the G-protein coupled cannabinoid CB(1) receptor. Recent studies have postulated the existence of carrier-mediated anandamide transport which is involved in the termination of the biological effects of anandamide. A membrane bound amidohydrolase (fatty acid amide hydrolase, FAAH), located intracellulary, hydrolyzes and inactivates anandamide and other endogenous cannabinoids such as 2-arachidonoylglycerol (2-AG). Structure-activity relationships (SARs) for endocannabinoid interaction with the CB receptors, the anandamide transporter and FAAH are currently emerging in the literature. This review considers the divergences between these SARs and focuses upon the conformational implications for endocannabinoid recognition at each of these biological targets.

Amidohydrolases↗
PubMed2000

Ligand-receptor signaling with endocannabinoids in preimplantation embryo development and implantation.

Although adverse effects of cannabinoids on pregnancy have been indicated for many years, the mechanisms by which they exert their actions were not clearly understood. Only recently, molecular and biochemical approaches have led to the identification of two types of cannabinoid receptors, brain-type receptors (CB1-R) and spleen-type receptors (CB2-R), which mediate cannabinoid effects. These findings were followed by the discovery of endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG). The natural cannabinoids and endocannabinoids exert their effects via cannabinoid receptors and share similar pharmacological and physiological properties. Recent demonstration of expression of functional CB1-R in the preimplantation embryo and synthesis of anandamide in the pregnant uterus of mice suggests that cannabinoid ligand-receptor signaling is operative in the regulation of preimplantation embryo development and implantation. This review describes recent observations and their significance in embryo-uterine interactions during implantation and future research directions in this emerging area of interest.

Animals↗
PubMed2002

Cell signaling by endocannabinoids and their congeners: questions of selectivity and other challenges.

The major endocannabinoids, anandamide (N-arachidonoylethanolamide, 20:4n-6 N-acylethanolamine) and 2-arachidonoylglycerol (2-AG) are structurally and functionally similar, but they are produced by different metabolic pathways and their levels must therefore be regulated by different mechanisms. Both endocannabinoids are accompanied by cannabinoid receptor-inactive, saturated and mono- or di-unsaturated congeners which can influence their metabolism and function. Here we review published data on the presence and production of anandamide and 2-AG and their congeners in mammalian cells and discuss this information in terms of their proposed signaling functions.

Animals↗
PubMed1999

Biosynthesis and inactivation of endocannabinoids: relevance to their proposed role as neuromodulators.

The two putative endogenous ligands of cannabinoid receptors, anandamide and 2-arachidonoylglycerol, are synthesized by and released from neurons in a Ca2+-dependent fashion, and re-uptaken and catabolized by both neurons and astrocytes. These biochemical features of the endocannabinoids, as well as some of their pharmacological effects in both central and peripheral nervous systems, suggest a role as neuromodulators for these metabolites. This neuromodulatory role is supported by the brain regional distribution of anandamide, its biosynthetic precursor and its major inactivating enzyme, and by the existence of possible regulatory mechanisms for the biosynthesis and inactivation of endocannabinoids, which are reviewed in this article.

Animals↗
PubMed2004

[News about therapeutic use of Cannabis and endocannabinoid system].

Growing basic research in recent years led to the discovery of the endocannabinoid system with a central role in neurobiology. New evidence suggests a therapeutic potential of cannabinoids in cancer chemotherapy-induced nausea and vomiting as well as in pain, spasticity and other symptoms in multiple sclerosis and movement disorders. Results of large randomized clinical trials of oral and sublingual Cannabis extracts will be known soon and there will be definitive answers to whether Cannabis has any therapeutic potential. Although the immediate future may lie in plant-based medicines, new targets for cannabinoid therapy focuses on the development of endocannabinoid degradation inhibitors which may offer site selectivity not afforded by cannabinoid receptor agonists.

Cannabinoid Receptor Modulators↗
PubMed2000

Cardiovascular effects of endocannabinoids--the plot thickens.

Cannabinoids, the bioactive ingredients of the marijuana plant, are best known for their psychoactive properties, but they also influence other physiological processes, such as cardiovascular variables. Endocannabinoids are recently identified lipid mediators that act as natural ligands at cannabinoid receptors and mimic most of the biological effects, including the cardiovascular actions, of plant-derived cannabinoids. In experimental animals, the most prominent component of the cardiovascular effects of cannabinoids is prolonged hypotension and bradycardia. This review focuses on the possible mechanisms underlying these effects. The emerging evidence suggesting that endocannabinoids may be involved in the peripheral regulation of vascular tone under certain conditions is also discussed.

Animals↗
PubMed2002

Endocannabinoid hydrolases.

Endocannabinoids (endogenous ligands of cannabinoid receptors) such as anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol (2-AG) are inactivated upon enzymatic hydrolysis. Recent progress in the enzymological and molecular biological studies on the 'endocannabinoid hydrolases' is reviewed in this article. Anandamide is hydrolyzed to arachidonic acid and ethanolamine by a membrane-bound amidase generally referred to as fatty acid amide hydrolase (FAAH). This enzyme has a broad substrate specificity, hydrolyzing oleamide (an endogenous sleep-inducing factor) and 2-AG as well as anandamide. cDNA cloning revealed that FAAH is composed of 579 amino acids and belongs to the amidase signature family. A serine residue functioning as a catalytic nucleophile and several other catalytically important residues were identified in its primary structure. Furthermore, recent generation and analysis of the FAAH gene-deficient mice demonstrated the central role of this enzyme in the metabolism of anandamide. Alternatively, an amidase, which is distinct from FAAH but also hydrolyzing anandamide and other N-acylethanolamines at acidic pH, was identified in human megakaryoblastic cells and rat organs such as lung and spleen. As for the 2-AG hydrolysis, in addition to the known monoacylglycerol lipase, other esterases and FAAH may be involved.

Amidohydrolases↗
PubMed2002

Tetrahydrocannabinol and endocannabinoids in feeding and appetite.

The physiological control of appetite and satiety, in which numerous neurotransmitters and neuropeptides play a role, is extremely complex. Here we describe the involvement of endocannabinoids in these processes. These endogenous neuromodulators enhance appetite in animals. The same effect is observed in animals and in humans with the psychotropic plant cannabinoid Delta(9)-tetrahydrocannabinol, which is an approved appetite-enhancing drug. The CB(1) cannabinoid receptor antagonist SR141716A blocks the effects on feeding produced by the endocannabinoids. If administered to mice pups, this antagonist blocks suckling. In obese humans, it causes weight reduction. Very little is known about the physiological and biochemical mechanisms involved in the effects of Delta(9)-tetrahydrocannabinol and the cannabinoids in feeding and appetite.

Animals↗
PubMed2001

Evidence for an endocannabinoid system in the central nervous system of the leech Hirudo medicinalis.

In invertebrates, like Hydra and sea urchins, evidence for a functional cannabinoid system was described. The partial characterization of a putative CB1 cannabinoid receptor in the leech Hirudo medicinalis led us to investigate the presence of a complete endogenous cannabinoid system in this organism. By using gas chromatography-mass spectrometry, we demonstrate the presence of the endocannabinoids anandamide (N-arachidonoylethanolamine, 21.5+/-0.7 pmol/g) and 2-arachidonoyl-glycerol (147.4+/-42.7 pmol/g), and of the biosynthetic precursor of anandamide, N-arachidonylphosphatidyl-ethanolamine (16.5+/-3.3 pmol/g), in the leech central nervous system (CNS). Anandamide-related molecules such as N-palmitoylethanolamine (32.4+/-1.6 pmol/g) and N-linolenoylethanolamine (5.8 pmol/g) were also detected. We also found an anandamide amidase activity in the leech CNS cytosolic fraction with a maximal activity at pH 7 and little sensitivity to typical fatty acid amide hydrolase (FAAH) inhibitors. Using an antiserum directed against the amidase signature sequence, we focused on the identification and the localization of the leech amidase. Firstly, leech nervous system protein extract was subjected to Western blot analysis, which showed three immunoreactive bands at ca. approximately 42, approximately 46 and approximately 66 kDa. The former and latter bands were very faint and were also detected in whole homogenates from the coelenterate Hydra vulgaris, where the presence of CB1-like receptors, endocannabinoids and a FAAH-like activity was reported previously. Secondly, amidase immunocytochemical detection revealed numerous immunoreactive neurons in the CNS of three species of leeches. In addition, we observed that leech amidase-like immunoreactivity matches to a certain extent with CB1-like immunoreactivity. Finally, we also found that stimulation by anandamide of this receptor leads, as in mammals, to inhibition of cAMP formation, although this effect appeared to be occurring through the previously described anandamide-induced and CB1-mediated activation of nitric oxide release. Taken together, these results suggest the existence of a complete and functional cannabinoid system in leeches.

Adenylyl Cyclases↗
PubMed2002

Endocannabinoids and cannabinoid receptor genetics.

This review presents the remarkable advances that have been achieved in marijuana (cannabinoid) research, with the discovery of specific receptors and the existence of naturally occurring cannabis-like substances in the human body and brain. The last decade has seen more rapid progress in marijuana research than any time in the thousands of years that marijuana has been used by humans, particularly in cannabinoid genomics. The cDNA and genomic sequences encoding G protein-coupled cannabinoid receptors (Cnrs) from several species have now been cloned. Endogenous cannabinoids (endocannabinoids), synthetic and hydrolyzing enzymes and transporters that define neurochemically-specific cannabinoid brain pathways have been identified. Endocannabinoid lipid signaling molecules alter activity at G protein-coupled receptors (GPCR) and possibly at anandamide-gated ion channels, such as vanilloid receptors. Availability of increasingly-specific CB1 and CB2 Cnr antagonists and of CB1 and CB2 Cnr knockout mice have increased our understanding of these cannabinoid systems and provides tantalizing evidence for even more G protein-coupled Cnrs. Initial studies of the Cnr gene structure, regulation and polymorphisms whet our appetite for more information about these interesting genes, their variants and roles in vulnerabilities to addictions and other neuropsychiatric disorders. Behavioral studies of cannabinoids document the complex interactions between rewarding and aversive effects of these drugs. Pursuing cannabinoid-related molecular, pharmacological and behavioral leads will add greatly to our understanding of endogenous brain neuromodulator systems, abused substances and potential therapeutics. This review of CB1 and CB2 Cnr genes in human and animal brain and their neurobiological effects provide a basis for many of these studies. Therefore, understanding the physiological cannabinoid control system in the human body and brain will contribute to elucidating this natural regulatory mechanism in health and disease.

Amino Acid Sequence↗
PubMed2002

Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids.

This review covers recent developments in the cellular neurophysiology of retrograde signaling in the mammalian central nervous system. Normally at a chemical synapse a neurotransmitter is released from the presynaptic element and diffuses to the postsynaptic element, where it binds to and activates receptors. In retrograde signaling a diffusible messenger is liberated from the postsynaptic element, and travels "backwards" across the synaptic cleft, where it activates receptors on the presynaptic cell. Receptors for retrograde messengers are usually located on or near the presynaptic nerve terminals, and their activation causes an alteration in synaptic transmitter release. Although often considered in the context of long-term synaptic plasticity, retrograde messengers have numerous roles on the short-term regulation of synaptic transmission. The focus of this review will be on a group of molecules from different chemical classes that appear to act as retrograde messengers. The evidence supporting their candidacy as retrograde messengers is considered and evaluated. Endocannabinoids have recently emerged as one of the most thoroughly investigated, and widely accepted, classes of retrograde messenger in the brain. The study of the endocannabinoids can therefore serve as a model for the investigation of other putative messengers, and most attention is devoted to a discussion of systems that use these new messenger molecules.

Animals↗