Suchergebnisse

The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic, and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology. ; This work was supported by INSERM, the University of Bordeaux and the Aquitaine Region (to VDG, PVP, GM, UM), by the Fondation pour la Recherche Medicale (DRM20101220445), the Human Frontiers Science Program, and the Agence Nationale de la Recherche (ANR Blanc ANR-13BSV4–0006-02) (to GM), the DG Research of the European Commission FP7 [#HEALTH-F2 2013–602891 (to RM), HEALTH-60319 and ERC–2010–StG–260515 (to GM)], the Spanish 'RETICS-Instituto de Salud Carlos III' (#RD12/0028/0023), the Spanish 'Ministerio de Ciencia e Innovación' (#SAF2011–29864, no. SAF2011–29864, #SAF2013-40592-R, no. SAF2013-40592-R) and the Catalan Government 'AGAUR-Generalitat de Catalunya' (#2009SGR00731 and #2014-SGR-1547) (to RM), The Basque Government grant BCG IT764-13, Ministerio de Economía y Competitividad (MINECO) grant BFU2012-33334, University of the Basque Country UPV/EHU UFI11/41 and Red de Trastornos Adictivos - Instituto de Salud Carlos III grant RD12/0028/0004 (to PG). The FEDER funds support is also acknowledged. EM-G was supported by a 'Sara Borrell' post-doctoral fellowship from the Spanish 'Instituto de Salud Carlos III'. FK was supported by an Aquitaine Region post-doctoral grant

Joint pain is a common clinical problem for which both inflammatory and degenerative joint diseases are major causes. The purpose of this study was to investigate the role of CB1 and CB2 cannabinoid receptors in the behavioral, histological, and neurochemical alterations associated with joint pain. The murine model of monosodium iodoacetate (MIA) was used to induce joint pain in knockout mice for CB1 (CB1KO) and CB2 cannabinoid receptors (CB2KO) and transgenic mice overexpressing CB2 receptors (CB2xP). In addition, we evaluated the changes induced by MIA in gene expression of CB1 and CB2 cannabinoid receptors and μ-, δ- and κ-opioid receptors in the lumbar spinal cord of these mice. Wild-type mice, as well as CB1KO, CB2KO, and CB2xP mice, developed mechanical allodynia in the ipsilateral paw after MIA intra-articular injection. CB1KO and CB2KO demonstrated similar levels of mechanical allodynia of that observed in wild-type mice in the ipsilateral paw, whereas allodynia was significantly attenuated in CB2xP. Interestingly, CB2KO displayed a contralateral mirror image of pain developing mechanical allodynia also in the contralateral paw. All mouse lines developed similar histological changes after MIA intra-articular injection. Nevertheless, MIA intra-articular injection produced specific changes in the expression of cannabinoid and opioid receptor genes in lumbar spinal cord sections that were further modulated by the genetic alteration of the cannabinoid receptor system. These results revealed that CB2 receptor plays a predominant role in the control of joint pain manifestations and is involved in the adaptive changes induced in the opioid system under this pain state. ; This work was supported by the Spanish "Ministerio de Ciencia e Innovación" (#SAF2007-64062), "Instituto de Salud Carlos III" (RETICS- Red de Trastornos Adictivos-Redes Temáticas de Investigación Cooperativa en Salud: #RD06/0001/0001, #RD06/0001/1004), Plan Nacional sobre Drogas (PNSD #2009/026), the Catalan Government (SGR2009-00131), the ICREA Foundation (ICREA Academia-2008), the DG Research of the European Commission (GENADDICT, # LSHM-CT-2004-05166, and PHECOMP, # LSHM-CT-2007-037669), CENIT program (CEN-20061005) from/nthe "Centro para el Desarollo Technológico Industrial" from the Spanish Ministry of Science and Innovation. Carmen La Porta (C.L.P) is a recipient of a predoctoral fellowship from the Spanish Ministry of Education. Auxiliadora Aracil-Fernández (A.A.F., predoctoral fellow) and Analía Rico (A.R., technician) are supported by RETICS. The partial support of FEDER funds (EU) is also acknowledged

Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited by the psychotropic side effects of ∆9-tetrahydrocannabinol (∆9-THC). Evidence is emerging for the therapeutic benefits of cannabis in the treatment of neurological and neurodegenerative diseases, with potential efficacy as an analgesic and antiemetic for the management of cancer-related pain and treatment-related nausea and vomiting, respectively. An increasing number of preclinical studies have established that ∆9-THC can inhibit the growth and proliferation of cancerous cells through the modulation of cannabinoid receptors (CB1R and CB2R), but clinical confirmation remains lacking. In parallel, the anti-cancer properties of non-THC cannabinoids, such as cannabidiol (CBD), are linked to the modulation of non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and ligand-regulated transcription factors, which together modulate oncogenic signalling and redox homeostasis. Additional evidence has also demonstrated the anti-inflammatory properties of cannabinoids, and this may prove relevant in the context of peritumoural oedema and the tumour immune microenvironment. This review aims to document the emerging mechanisms of anti-cancer actions of non-THC cannabinoids.

Cannabinoids' usefulness in the treatment of neurological disorders (epilepsy, and various neurodegenerative diseases, such as Multiple Sclerosis and Alzheimer's Disease) has been demonstrated in a growing number of studies. Of the 11 known general types of natural cannabinoids, the focus has been mainly directed at cannabidiol (CBD) due to its specificity in stimulating cannabinoid receptors and the low rate of side effects, as well as on Δ (9)-tetrahydrocannabinol (Δ9-THC). The natural and synthetic analogs of CBD have been described as a potential treatment in neurological diseases, as they showed their therapeutic benefits in reducing the seizures from epilepsy and their neuroprotectivity in neurodegenerative diseases. First and foremost, CBD's neuroprotective properties are due to its capacity to act as an endogenous cannabinoid receptor agonist. Second, CBD enhances neuroprotection by interacting with many signal transduction pathways mediated indirectly through cannabinoid receptors. CBD also reduces the hyperphosphorylation of glycogen synthetase kinase 3 (GSK-3) induced by the buildup of Amyloid β in the physiopathology of Alzheimer's disease.

The field of cannabinoid research has been receiving ever-growing interest. Ongoing debates worldwide about the legislation of medical cannabis further motivates research into cannabinoid function within the central nervous system (CNS). To date, two well-characterized cannabinoid receptors exist. While most research has investigated Cb-1 receptors (Cb(1)Rs), Cb-2 receptors (Cb(2)Rs) in the brain have started to attract considerable interest in recent years. With indisputable evidence showing the wide-distribution of Cb(2)Rs in the brain of different species, they are no longer considered just peripheral receptors. However, in contrast to Cb(1)Rs, the functionality of central Cb(2)Rs remains largely unexplored. Here we review recent studies on hippocampal Cb(2)Rs. While conflicting results about their function have been reported, we have made significant progress in understanding the involvement of Cb(2)Rs in modulating cellular properties and network excitability. Moreover, Cb(2)Rs have been shown to be expressed in different subregions of the hippocampus, challenging our prior understanding of the endocannabinoid system. Although more insight into their functional roles is necessary, we propose that targeting hippocampal Cb(2)Rs may offer novel therapies for diseases related to memory and adult neurogenesis deficits.

Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited by the psychotropic side effects of ∆ 9 -tetrahydrocannabinol (∆ 9 -THC). Evidence is emerging for the therapeutic benefits of cannabis in the treatment of neurological and neurodegenerative diseases, with potential efficacy as an analgesic and antiemetic for the management of cancer-related pain and treatment-related nausea and vomiting, respectively. An increasing number of preclinical studies have established that ∆ 9 -THC can inhibit the growth and proliferation of cancerous cells through the modulation of cannabinoid receptors (CB1R and CB2R), but clinical confirmation remains lacking. In parallel, the anti-cancer properties of non-THC cannabinoids, such as cannabidiol (CBD), are linked to the modulation of non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and ligand-regulated transcription factors, which together modulate oncogenic signalling and redox homeostasis. Additional evidence has also demonstrated the anti-inflammatory properties of cannabinoids, and this may prove relevant in the context of peritumoural oedema and the tumour immune microenvironment. This review aims to document the emerging mechanisms of anti-cancer actions of non-THC cannabinoids.

Simple Summary: This review analyses the complex involvement of the various components of the endocannabinoid system (ECS) in the susceptibility to cancer, prognosis, and response to treatment, focusing on its relationship with cancer biology in selected solid cancers (breast, gastrointestinal, gynaecological, prostate cancer, thoracic, thyroid, central nervous system (CNS) tumours, and melanoma). The same ECS component can exert both protective and pathogenic effects in different tumour subtypes, which are often pathologically driven by different biological factors. Although an attractive target in cancer, the use of components in anti-cancer treatment is still interlinked with many legal and ethical issues that need to be considered. The legislation which outlines the permissive boundaries of their therapeutic use in oncology is still unable to follow the current scientific burden of evidence, but the number of ongoing clinical trials might tip the scale forward in the near future. ; This work was supported by the "Ministerio de Economía y Competitividad" and European Regional Development Funds of the European Union (Grant No. SAF2017-87629-R) and the Ministry of Education,Science and Technological Development of the Republic of Serbia (451-03-68/2020-14/200043).

большинство синтетических каннабиноидов (SC) ; принадлежит к группе т.н. дизайнерских наркотиков ; распространяемых через нелегальные интернет-магазины. Первые сообщения о данной группе психоактивных веществ появились в 70-х годах прошлого века. На сегодняшний день по разным подсчетам насчитывается более 160 разновидностей синтетических каннабиноидов ; и эта цифра ежегодно увеличивается за счет синтеза новых веществ данной группы. Данная группа психоактивных веществ создана для «копирования» психоактивных эффектов каннабиса. Изначально данные вещества создавались исключительно в научных целях ; для исследования эндоканнабиноидной системы человека. Натуральный ТГК является частичным агонистом каннабиноидных рецепторов. Синтетические каннабиноиды являются полными агонистами каннабиноидных рецепторов CB1R и CB2R типов. Большинство стран в мире ; включая Россию ; на законодательном уровне приняли меры ограничительного характера для препятствования распространению данной группы психоактивных веществ. Для того чтобы обойти меры законодательного характера ; производители синтетических каннабиноидов регулярно меняют химическую формулу. Ежегодно растет число неотложных госпитализаций ; связанных с употреблением синтетических каннабиноидов ; в рецензируемой литературе описаны летальные исходы ; непосредственно связанные с соматическими осложнениями после употребления. Многочисленными исследованиями доказана возможность развития психической зависимости вследствие употребления синтетических каннабиноидов. Предлагаемый обзор литературы представлен с целью систематизации данных в области изучения синтетических каннабиноидов. ; the majority of synthetic cannabinoids (SC) ; belongs to the group of so-called designer drugs distributed through illegal online shopping. The first reports of this group of psychoactive substances appeared in the 70s of the last century. Today ; according to various estimates ; there are over 160 varieties of synthetic cannabinoids ; and this figure is increasing annually due to the synthesis of new substances in the group. This group of substances is designed to «copy» the psychoactive effects of cannabis. Initially ; these substances were created solely for research purposes ; to study the endocannabinoid system of the person. Natural THC is a partial agonist of cannabinoid receptors. Synthetic cannabinoids are full agonists CB1R and CB2R types of cannabinoid receptors. Most countries in the world ; including Russia ; at the legislative level have taken restrictive measures for preventing the spread of this group of substances. In order to circumvent the legislative measures ; the producers of synthetic cannabinoids regularly changing the chemical formula. Each year ; an increasing number of emergency hospital admissions associated with the use of synthetic cannabinoids in the peer-reviewed literature describes the deaths directly attributable to medical complications after taking synthetic cannabinoids. Numerous studies have proven the possibility of developing psychological dependence due to the use of synthetic cannabinoids. The proposed review of the literature is presented for the purpose of organizing data in the field of synthetic cannabinoids.

Mental disorders have a high prevalence compared with many other health conditions and are the leading cause of disability worldwide. Several studies performed in the last years support the involvement of the endocannabinoid system in the etiopathogenesis of different mental disorders. The present review will summarize the latest information on the role of the endocannabinoid system in psychiatric disorders, specifically depression, anxiety, and schizophrenia. We will focus on the findings from human brain studies regarding alterations in endocannabinoid levels, cannabinoid receptors and endocannabinoid metabolizing enzymes in patients suffering mental disorders. Studies carried out in humans have consistently demonstrated that the endocannabinoid system is fundamental for emotional homeostasis and cognitive function. Thus, deregulation of the different elements that are part of the endocannabinoid system may contribute to the pathophysiology of several mental disorders. However, the results reported are controversial. In this sense, different alterations in gene and/or protein expression of CB1 receptors have been shown depending on the technical approach used or the brain region studied. Despite the current discrepancies regarding cannabinoid receptors changes in depression and schizophrenia, present findings point to the endocannabinoid system as a pivotal neuromodulatory pathway relevant in the pathophysiology of mental disorders. ; This study was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-67457-R, MINECO/FEDER), the Plan Estatal de I+D+i 2013-2016, the Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación, Spanish Ministry of Economy, FEDER (PI13/01529) and the Basque Government (IT616/13). I I-L is a recipient of a Predoctoral Fellowship from the Basque Government. E F-Z is a recipient of a Predoctoral Fellowship from the University of Cantabria. CM is a recipient of a Postdoctoral Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2016, ID 747487).

The number of annual cannabinoid users exceeds 100,000,000 globally and an estimated 9 % of these individuals will suffer from dependency. Although exogenous cannabinoids, like those contained in marijuana, are known to exert their effects by disrupting the endocannabinoid system, a dearth of knowledge exists about the potential toxicological consequences on public health. Conversely, the endocannabinoid system represents a promising therapeutic target for a plethora of disorders because it functions to endogenously regulate a vast repertoire of physiological functions. Accordingly, the rapidly expanding field of cannabinoid biology has sought to leverage model organisms in order to provide both toxicological and therapeutic insights about altered endocannabinoid signaling. The primary goal of this manuscript is to review the existing field of cannabinoid research in the genetically tractable zebrafish model—focusing on the cannabinoid receptor genes, cnr1 and cnr2, and the genes that produce enzymes for synthesis and degradation of the cognate ligands anandamide and 2-arachidonylglycerol. Consideration is also given to research that has studied the effects of exposure to exogenous phytocannabinoids and synthetic cannabinoids that are known to interact with cannabinoid receptors. These results are considered in the context of either endocannabinoid gene expression or endocannabinoid gene function, and are integrated with findings from rodent studies. This provides the framework for a discussion of how zebrafish may be leveraged in the future to provide novel toxicological and therapeutic insights in the field of cannabinoid biology, which has become increasingly significant given recent trends in cannabis legislation.

<b><i>Background:</i></b> Synthetic cannabinoids are compounds that bind cannabinoid receptors with a high potency and have been used widely in Europe by young people. However, little is known about the pharmacology and morphological effects of this group of substances in the brain. This study is aimed at investigating the morphological differences among synthetic cannabinoids users and healthy controls. <b><i>Methods:</i></b> Voxel-based morphometry was used to investigate the differences in brain tissue composition in 20 patients with synthetic cannabinoids use and 20 healthy controls. All participants were male. <b><i>Results:</i></b> Compared to healthy controls, voxel of interest analyses showed that regional grey matter volume in both left and right thalamus and left cerebellum was significantly reduced in synthetic cannabinoids users (p < 0.05). No correlation has been found between the age of first cannabis use, duration of use, frequency of use and grey matter volume. <b><i>Discussion:</i></b> These preliminary results suggest an evidence of some structural differences in the brain of synthetic cannabinoids users, and point the need for further investigation of morphological effects of synthetic cannabinoids in the brain.

Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited by the psychotropic side effects of ∆(9)-tetrahydrocannabinol (∆(9)-THC). Evidence is emerging for the therapeutic benefits of cannabis in the treatment of neurological and neurodegenerative diseases, with potential efficacy as an analgesic and antiemetic for the management of cancer-related pain and treatment-related nausea and vomiting, respectively. An increasing number of preclinical studies have established that ∆(9)-THC can inhibit the growth and proliferation of cancerous cells through the modulation of cannabinoid receptors (CB1R and CB2R), but clinical confirmation remains lacking. In parallel, the anti-cancer properties of non-THC cannabinoids, such as cannabidiol (CBD), are linked to the modulation of non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and ligand-regulated transcription factors, which together modulate oncogenic signalling and redox homeostasis. Additional evidence has also demonstrated the anti-inflammatory properties of cannabinoids, and this may prove relevant in the context of peritumoural oedema and the tumour immune microenvironment. This review aims to document the emerging mechanisms of anti-cancer actions of non-THC cannabinoids.