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A glioma is a type of tumor that acts on the Central Nervous System (CNS) in a highly aggressive manner. Gliomas can occasionally be inaccurately diagnosed and treatments have low efficacy, meaning that patients exhibit a survival of less than one year after diagnosis. Due to factors such as intratumoral cell variability, inefficient chemotherapy drugs, adaptive resistance development to drugs and tumor recurrence after resection, the search continues for new drugs that can inhibit glioma cell growth. As such, analogues of endocannabinoids, such as fatty acid amides (FAAs), represent interesting alternatives for inhibiting tumor growth, since FAAs can modulate several metabolic pathways linked to cancer and, thus, may hold potential for managing glioblastoma. The aim of this study was to investigate the in vitro effects of two fatty ethanolamides (FAA1 and FAA2), synthetized via direct amidation from andiroba oil (Carapa guianensis Aublet), on C6 glioma cells. FAA1 and FAA2 reduced C6 cell viability, proliferation and migratory potential in a dose-dependent manner and were not toxic to normal retina glial cells. Both FAAs caused apoptotic cell death through the loss of mitochondrial integrity (ΔΨm), probably by activating cannabinoid receptors, and inhibiting the PI3K/Akt pathway. In conclusion, FAAs derived from natural products may have the potential to treat glioma-type brain cancer.

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Background: Of the seventy million people who suffer from epilepsy, 40 percent of them become resistant to more than one antiepileptic medication and have a higher chance of death. While the classical definition of epilepsy was due to the imbalance between excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA)-ergic signalling, substantial evidence implicates muscarinic receptors in the regulation of neural excitability. Summary: Cannabinoids have shown to reduce seizure activity and neuronal excitability in several epileptic models through the activation of muscarinic receptors with drugs which modulate their activity. Cannabinoids also have been effective in reducing antiepileptic activity in pharmaco-resistant individuals; however, the mechanism of its effects in temporal lobe epilepsy is not clear. Key Messages: This review seeks to elucidate the relationship between muscarinic and cannabinoid receptors in epilepsy and neural excitability.

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Abstract MCH1 is a synthetic macamide that has shown in vitro inhibitory activity on fatty acid amide hydrolase (FAAH), an enzyme responsible for endocannabinoid metabolism. This inhibition can modulate endocannabinoid and dopamine signaling in the nucleus accumbens (NAc), potentially having an antidepressant-like effect. The present study aimed to evaluate the effect of the in vivo administration of MCH1 (3, 10, and 30 mg/kg, ip) in 2-month-old BALB/c male mice (n=97) on forced swimming test (FST), light-dark box (LDB), and open field test (OFT) and on early gene expression changes 2 h after drug injection related to the endocannabinoid system (Cnr1 and Faah) and dopaminergic signaling (Drd1 and Drd2) in the NAc core. We found that the 10 mg/kg MCH1 dose reduced the immobility time compared to the vehicle group in the FST with no effect on anxiety-like behaviors measured in the LDB or OFT. However, a 10 mg/kg MCH1 dose increased locomotor activity in the OFT compared to the vehicle. Moreover, RT-qPCR results showed that the 30 mg/kg MCH1 dose increased Faah gene expression by 2.8-fold, and 10 mg/kg MCH1 increased the Cnr1 gene expression by 4.3-fold compared to the vehicle. No changes were observed in the expression of the Drd1 and Drd2 genes in the NAc at either MCH1 dose. These results indicated that MCH1 might have an antidepressant-like effect without an anxiogenic effect and induces significant changes in endocannabinoid-related genes but not in genes of the dopaminergic signaling system in the NAc of mice.

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Introducción: Los endocannabinoides son una diana en el tratamiento de la obesidad y se producen a partir de ácidos grasos esenciales, los derivados del ácido linoleico actúan como agonistas de los receptores cannabinoides tipo 1 (CB1), asimismo, los derivados del ácido linolénico ejercen efectos de antagonistas de dichos receptores, por lo cual se plantea que modificar el consumo dietario de los ácidos grasos omega 3 y 6 podría modular la activación del sistema endocannabinoide, lo que podría ser favorable para personas con adicción a la comida, considerando cómo este sistema promueve la actividad de las vías dopaminérgicas que se alteran en la adicción a sustancias psicoactivas. Objetivo: Analizar la correlación entre el puntaje de adicción a la comida por la escala mYFAS 2.0 y los niveles plasmáticos de ácido araquidónico en adultos con obesidad tras modular la ingesta de alimentos fuente de ácidos grasos esenciales. Metodología: Se desarrolló un estudio piloto con diseño de ensayo clínico cruzado en dos tiempos, en donde los participantes recibieron los tratamientos estándar y experimental, en estos se brindaron planes siguiendo recomendaciones para el manejo nutricional de la obesidad, adicionalmente, el tratamiento experimental contó con pautas para disminuir el consumo del Omega 6 y aumentar el consumo de Omega 3 para obtener una relación menor a 5:1 entre estos ácidos grasos. Resultados: Se observó una disminución significativa en el puntaje de adicción a la comida y los niveles plasmáticos de ácido araquidónico en los participantes tras recibir el tratamiento experimental, presentando una correlación directamente proporcional entre estas, por otro lado, el tratamiento estándar estuvo asociado a una correlación inversamente proporcional entre estos. Conclusiones: El descenso en las concentraciones plasmáticas del ácido araquidónico fue asociado a un menor puntaje en la escala mYFAS 2.0 de adicción a la comida en los participantes de este estudio tras su exposición al tratamiento experimental.

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Introduction: Endocannabinoids are a target in obesity treatment and they are produced from the essential fatty acids, the metabolites of linoleic acid act as agonists of the cannabinoid receptors type 1 (CB1), likewise, the metabolites of the linolenic acid act as inverse agonists of such receptors, hence, it is proposed that modifying the dietary intake of the essential fatty acids (Omega 6 and 3) may modulate the activation of the endocannabinoid system, this could be favorable for people with food addiction, considering how this system promotes the activity of the dopaminergic pathways that are altered in the psychoactive substances addiction. Objective: To analyze the correlation between the food addiction score and plasmatic levels of arachidonic acid in adults with obesity following a modulation of the dietary intake of essential fatty acids n-6 and n-3 food sources. Methods: A pilot study was carried out with a two-period crossover clinical trial design, in which the participants received standard and experimental treatments, in these programs, plans were provided following guidelines for the nutritional management of obesity, in addition, the experimental treatment included recommendations to reduce the intake of linoleic acid and to increase the intake of linolenic acid to obtain a ratio lower to 5:1 between these fatty acids. Results: A significant decrease in the food addiction score and plasmatic levels of arachidonic acid was observed in the participants exposed to the experimental treatment, showing a directly proportional correlation, moreover, the standard treatment was associated to inverse correlations between these variables. Conclusion: The decrease in plasmatic arachidonic acid levels was associated with lower scores on the mYFAS 2.0 of food addiction in the participants of this study following their exposure to the experimental treatment.

Assuntos

Humanos , Ácido Araquidônico , Ciências da Nutrição , Dependência de Alimentos , Obesidade , Ácidos Graxos Ômega-6 , Endocanabinoides

RESUMO

The kynurenine pathway (KP) and the endocannabinoid system (ECS) are known to be deregulated in depression and obesity; however, it has been recognized that acute physical exercise has an important modulating role inducing changes in the mobilization of their respective metabolites-endocannabinoids (eCBs) and kynurenines (KYNs)-which overlap at some points, acting as important antidepressant, anti-nociceptive, anti-inflammatory, and antioxidant biomarkers. Therefore, the aim of this review is to analyze and discuss some recently performed studies to investigate the potential interactions between both systems, particularly those related to exercise-derived endocannabinoidome and kynurenine mechanisms, and to elucidate how prescription of physical exercise could represent a new approach for the clinical management of these two conditions.

RESUMO

Sepsis is associated with several comorbidities in survivors, such as posttraumatic stress disorder (PTSD). This study investigated whether rats that survive sepsis develop the generalization of fear memory as a model of PTSD. Responses to interventions that target the endothelin-1 (ET-1)/cannabinoid system and glial activation in the initial stages of sepsis were evaluated. As a control, we evaluated hyperalgesia before fear conditioning. Sepsis was induced by cecal ligation and puncture (CLP) in Wistar rats. CLP-induced sepsis with one or three punctures resulted in fear generalization in the survivors 13 and 20 days after the CLP procedure, a process that was not associated with hyperalgesia. Septic animals were intracerebroventricularly treated with vehicle, the endothelin receptor A (ETA) antagonist BQ123, the cannabinoid CB1 and CB2 receptor antagonists AM251 and AM630, respectively, and the glial blocker minocycline 4 h after CLP. The blockade of either CB1 or ETA receptors increased the survival rate, but only the former reversed fear memory generalization. The endothelinergic system blockade is important for improving survival but not for fear memory. Treatment with the CB2 receptor antagonist or minocycline also reversed the generalization of fear memory but did not increase the survival rate that was associated with CLP. Minocycline treatment also reduced tumor necrosis factor-α levels in the hippocampus suggesting that neuroinflammation is important for the generalization of fear memory induced by CLP. The influence of CLP on the generalization of fear memory was not related to Arc protein expression, a regulator of synaptic plasticity, in the dorsal hippocampus.

Assuntos

Canabinoides , Sepse , Transtornos de Estresse Pós-Traumáticos , Ratos , Animais , Receptores de Canabinoides , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Ratos Wistar , Doenças Neuroinflamatórias , Minociclina , Hiperalgesia , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Sepse/metabolismo

RESUMO

Graft-versus-host disease (GVHD) is a serious inflammatory illness that often occurs as a secondary complication of bone marrow transplantation. Current therapies have limited effectiveness and fail to achieve a balance between inflammation and the graft-versus-tumor effect. In this study, we investigate the effects of the endocannabinoid anandamide on the complex pathology of GVHD. We assess the effects of an irreversible inhibitor of fatty acid amine hydrolase or exogenous anandamide and find that they increase survival and reduce clinical signs in GVHD mice. In the intestine of GVHD mice, treatment with exogenous anandamide also leads to a reduction in the number of CD3+, CD3+CD4+, and CD3+CD8+ cells, which reduces the activation of CD3+CD4+ and CD3+CD8+ cells, as assessed by enhanced CD28 expression, a T cell co-stimulatory molecule. Exogenous AEA was also able to reduce TNF-α and increase IL-10 in the intestine of GVHD mice. In the liver, exogenous AEA reduces injury, TNF-α levels, and the number of CD3+CD8+ cells. Interestingly, anandamide reduces Mac-1α, which lowers the adhesion of transplanted cells in mesenteric veins. These effects are mimicked by JWH133-a CB2 selective agonist-and abolished by treatment with a CB2 antagonist. Furthermore, the effects caused by anandamide treatment on survival were related to the CB2 receptor, as the CB2 antagonist abolished it. This study shows the critical role of the CB2 receptor in the modulation of the inflammatory response of GVHD by treatment with anandamide, the most prominent endocannabinoid.

Assuntos

Endocanabinoides , Doença Enxerto-Hospedeiro , Animais , Camundongos , Endocanabinoides/farmacologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Intestinos , Linfócitos/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Fator de Necrose Tumoral alfa

RESUMO

The endocannabinoid system (ECS) plays a key neuromodulatory role in the brain. Main features of endocannabinoids (eCBs) are that they are produced on demand, in response to enhanced neuronal activity, act as retrograde messengers, and participate in the induction of brain plasticity processes. Sexual activity is a motivated behavior and therefore, the mesolimbic dopaminergic system (MSL) plays a central role in the control of its appetitive component (drive to engage in copulation). In turn, copulation activates mesolimbic dopamine neurons and repeated copulation produces the continuous activation of the MSL system. Sustained sexual activity leads to the achievement of sexual satiety, which main outcome is the transient transformation of sexually active male rats into sexually inhibited animals. Thus, 24 h after copulation to satiety, the sexually satiated males exhibit a decreased sexual motivation and do not respond to the presence of a sexually receptive female with sexual activity. Interestingly, blockade of cannabinoid receptor 1 (CB1R) during the copulation to satiety process, interferes with both the appearance of the long-lasting sexual inhibition and the decrease in sexual motivation in the sexually satiated males. This effect is reproduced when blocking CB1R at the ventral tegmental area evidencing the involvement of MSL eCBs in the induction of this sexual inhibitory state. Here we review the available evidence regarding the effects of cannabinoids, including exogenously administered eCBs, on male rodent sexual behavior of both sexually competent animals and rat sub populations spontaneously showing copulatory deficits, considered useful to model some human male sexual dysfunctions. We also include the effects of cannabis preparations on human male sexual activity. Finally, we review the role played by the ECS in the control of male sexual behavior expression with the aid of the sexual satiety phenomenon. Sexual satiety appears as a suitable model for the study of the relationship between eCB signaling, MSL synaptic plasticity and the modulation of male sexual motivation under physiological conditions that might be useful for the understanding of MSL functioning, eCB-mediated plasticity and their relationship with motivational processes.

RESUMO

Pannexin-1 (Panx1) hemichannel is a non-selective transmembrane channel that may play important roles in intercellular signaling by allowing the permeation of ions and metabolites, such as ATP. Although recent evidence shows that the Panx1 hemichannel is involved in controlling excitatory synaptic transmission, the role of Panx1 in inhibitory transmission remains unknown. Here, we studied the contribution of Panx1 to the GABAergic synaptic efficacy onto CA1 pyramidal neurons (PyNs) by using patch-clamp recordings and pharmacological approaches in wild-type and Panx1 knock-out (Panx1-KO) mice. We reported that blockage of the Panx1 hemichannel with the mimetic peptide 10Panx1 increases the synaptic level of endocannabinoids (eCB) and the activation of cannabinoid receptors type 1 (CB1Rs), which results in a decrease in hippocampal GABAergic efficacy, shifting excitation/inhibition (E/I) balance toward excitation and facilitating the induction of long-term potentiation. Our finding provides important insight unveiling that Panx1 can strongly influence the overall neuronal excitability and play a key role in shaping synaptic changes affecting the amplitude and direction of plasticity, as well as learning and memory processes.

Assuntos

Hipocampo , Proteínas do Tecido Nervoso , Plasticidade Neuronal , Células Piramidais , Animais , Camundongos , Conexinas/genética , Conexinas/metabolismo , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Transmissão Sináptica

RESUMO

Allergic reactions are highly prevalent pathologies initiated by the production of IgE antibodies against harmless antigens (allergens) and the activation of the high-affinity IgE receptor (FcεRI) expressed in the surface of basophils and mast cells (MCs). Research on the mechanisms of negative control of those exacerbated inflammatory reactions has been intense in recent years. Endocannabinoids (eCBs) show important regulatory effects on MC-mediated immune responses, mainly inhibiting the production of pro-inflammatory mediators. However, the description of the molecular mechanisms involved in eCB control of MC activation is far from complete. In this review, we aim to summarize the available information regarding the role of eCBs in the modulation of FcεRI-dependent activation of that cell type, emphasizing the description of the eCB system and the existence of some of its elements in MCs. Unique characteristics of the eCB system and cannabinoid receptors (CBRs) localization and signaling in MCs are mentioned. The described and putative points of cross-talk between CBRs and FcεRI signaling cascades are also presented. Finally, we discuss some important considerations in the study of the effects of eCBs in MCs and the perspectives in the field.

Assuntos

Hipersensibilidade , Receptores de IgE , Humanos , Receptores de IgE/metabolismo , Imunoglobulina E/metabolismo , Imunoglobulina E/farmacologia , Endocanabinoides/metabolismo , Endocanabinoides/farmacologia , Mastócitos/metabolismo , Hipersensibilidade/metabolismo

RESUMO

The endocannabinoid system (ECS) refers to a complex cell-signaling system highly conserved among species formed by numerous receptors, lipid mediators (endocannabinoids) and synthetic and degradative enzymes. It is widely distributed throughout the body including the CNS, where it participates in synaptic signaling, plasticity and neurodevelopment. Besides, the olfactory ensheathing glia (OEG) present in the olfactory system is also known to play an important role in the promotion of axonal growth and/or myelination. Therefore, both OEG and the ECS promote neurogenesis and oligodendrogenesis in the CNS. Here, we investigated if the ECS is expressed in cultured OEG, by assessing the main markers of the ECS through immunofluorescence, western blotting and qRT-PCR and quantifying the content of endocannabinoids in the conditioned medium of these cells. After that, we investigated whether the production and release of endocannabinoids regulate the differentiation of oligodendrocytes co-cultured with hippocampal neurons, through Sholl analysis in oligodendrocytes expressing O4 and MBP markers. Additionally, we evaluated through western blotting the modulation of downstream pathways such as PI3K/Akt/mTOR and ERK/MAPK, being known to be involved in the proliferation and differentiation of oligodendrocytes and activated by CB1, which is the major endocannabinoid responsive receptor in the brain. Our data show that OEG expresses key genes of the ECS, including the CB1 receptor, FAAH and MAGL. Besides, we were able to identify AEA, 2-AG and AEA related mediators palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in the conditioned medium of OEG cultures. These cultures were also treated with URB597 10-9 M, a FAAH selective inhibitor, or JZL184 10-9 M, a MAGL selective inhibitor, which led to the increase in the concentrations of OEA and 2-AG in the conditioned medium. Moreover, we found that the addition of OEG conditioned medium (OEGCM) enhanced the complexity of oligodendrocyte process branching in hippocampal mixed cell cultures and that this effect was inhibited by AM251 10-6 M, a CB1 receptor antagonist. However, treatment with the conditioned medium enriched with OEA or 2-AG did not alter the process branching complexity of premyelinating oligodendrocytes, while decreased the branching complexity in mature oligodendrocytes. We also observed no change in the phosphorylation of Akt and ERK 44/42 in any of the conditions used. In conclusion, our data show that the ECS modulates the number and maturation of oligodendrocytes in hippocampal mixed cell cultures.

RESUMO

Studies in recent years have shown that the endocannabinoid (eCB) system is activated by exercise and modulates several physiological processes. Thus, the present review aimed to summarize the literature about the involvement of the eCB system in the control of pain, obesity, and metabolism by exercise. MEDLINE, EMBASE, and Web of Science were searched for experimental studies that investigated the presence of the eCB system in animal models of pain and obesity, in which the animals were subjected to different exercise modalities. The primary outcomes were pain, obesity, and metabolism. The databases were searched for articles from their inception up until March 2020. Two independent reviewers extracted the data and assessed the methodological quality of the included studies. Thirteen studies were considered eligible for this review. The results indicated that there was increased expression and levels of cannabinoid receptors and eCBs, respectively, after aerobic and resistance exercise, and that this effect was associated with antinociception. The eCB system was modulated by exercise in obese rats, confirming that it may also be involved in the control of obesity and metabolism when these are modulated by aerobic training. Exercise can be effective in controlling pain, partly through the involvement of the eCB system. In addition, exercise can modulate the imbalance of the eCB system in obesity and metabolic disorders, thus also controlling these pathologies through this signaling system.

Assuntos

Endocanabinoides , Roedores , Ratos , Animais , Endocanabinoides/metabolismo , Roedores/metabolismo , Obesidade/metabolismo , Receptores de Canabinoides/metabolismo , Dor

RESUMO

Active principles extracted from plants, such as essential oils, have been commonly described in the literature as therapeutic targets for numerous pathological conditions. Cannabis sativa, which has an ancient and peculiar history, has been used for various purposes, from recreational to compounds of pharmacotherapeutic and industrial importance, such as pesticides based on this plant. It is a plant that contains approximately 500 described cannabinoid compounds and is the target of in vitro and in vivo studies at different locations. This review clarifies the role of cannabinoid compounds in parasitic infections caused by helminths and protozoa. In addition, this study briefly presented the use of C. sativa constituents in the formulation of pesticides for vector control, as the latter topic is justified by the economic burden faced by several regions where vector-borne diseases are a troubling reality. Studies involving cannabis compounds with pesticidal potential should be encouraged, especially those that evaluate their effectiveness against the different life cycles of insects, seeking to interrupt vector proliferation after egg laying. Actions aimed at the management and cultivation of plant species with ecologically correct pharmacotherapeutic and pesticide potentials are becoming urgent.

Assuntos

Canabinoides , Cannabis , Helmintos , Animais , Estrutura Molecular , Plantas , Insetos Vetores

RESUMO

Skeletal muscle is the largest tissue in the human body, comprising approximately 40% of body mass. After damage or injury, a healthy skeletal muscle is often fully regenerated; however, with aging and chronic diseases, the regeneration process is usually incomplete, resulting in the formation of fibrotic tissue, infiltration of intermuscular adipose tissue, and loss of muscle mass and strength, leading to a reduction in functional performance and quality of life. Accumulating evidence has shown that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and their lipid mediators (i.e., oxylipins and endocannabinoids) have the potential to enhance muscle regeneration by positively modulating the local and systemic inflammatory response to muscle injury. This review explores the process of muscle regeneration and how it is affected by acute and chronic inflammatory conditions, focusing on the potential role of n-3 PUFAs and their derivatives as positive modulators of skeletal muscle healing and regeneration.

Assuntos

Ácidos Graxos Ômega-3 , Qualidade de Vida , Humanos , Oxilipinas , Músculo Esquelético , Regeneração , Ácidos Graxos

RESUMO

Chemotherapy-induced neuropathic pain is a serious clinical problem and one of the major side effects in cancer treatment. The endocannabinoid system (ECS) plays a crucial role in regulating pain neurotransmission, and changes in the expression of different components of the ECS have been reported in experimental models of persistent pain. In addition, sex differences have been observed in ECS regulation and function. The aim of our study was to evaluate whether administration of oxaliplatin, a neurotoxic antineoplastic agent, induced changes in the expression of ECS components in peripheral and central stations of the pain pathway, and if those changes exhibited sexual dimorphism. Adult male and female rats were injected with oxaliplatin or saline, and mechanical and cold hypersensitivity and allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels corresponding to cannabinoid receptors (CB1, CB2), cannabinoid-related receptors (GPR55, 5HT1A, TRPV1) and to the main enzymes involved in the synthesis (DAGL, DAGL, NAPE-PLD) and degradation (MGL, FAAH) of endocannabinoids were assessed in lumbar dorsal root ganglia (DRGs) and spinal cord by using real time RT-PCR. In addition, the levels of the main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), were evaluated using commercial ELISA kits. Oxaliplatin administration induced the development of mechanical and cold hypersensitivity and allodynia in male and female animals. Oxaliplatin also induced early and robust changes in the expression of several components of the ECS in DRGs. A marked upregulation of CB1, CB2, 5HT1A and TRPV1 was detected in both sexes. Interestingly, while DAGL mRNA levels remained unchanged, DAGL was downregulated in male and upregulated in female rats. Finally, MGL and NAPE-PLD showed increased levels only in male animals, while FAAH resulted upregulated in both sexes. In parallel, reduced 2-AG and AEA levels were detected in DRGs from male or female rats, respectively. In the lumbar spinal cord, only TRPV1 mRNA levels were found to be upregulated in both sexes. Our results reveal previously unreported changes in the expression of cannabinoid receptors, ligands and enzymes occurring mainly in the peripheral nervous system and displaying certain sexual dimorphism. These changes may contribute to the physiopathology of oxaliplatin-induced neuropathic pain in male and female rats. A better understanding of these dynamic changes will facilitate the development of mechanism- and sex-specific approaches to optimize the use of cannabinoid-based medicines for the treatment of chemotherapy-induced pain.

Assuntos

Antineoplásicos , Canabinoides , Neuralgia , Feminino , Masculino , Ratos , Animais , Endocanabinoides/metabolismo , Endocanabinoides/uso terapêutico , Caracteres Sexuais , Hiperalgesia/metabolismo , Oxaliplatina/toxicidade , Canais de Cátion TRPV/metabolismo , Neuralgia/metabolismo , Receptores de Canabinoides/metabolismo , Antineoplásicos/toxicidade , Antineoplásicos/uso terapêutico , RNA Mensageiro , Modelos Teóricos , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/uso terapêutico , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo

RESUMO

The active principles of Cannabis sativa are potential treatments for several diseases, such as pain, seizures and anorexia. With the increase in the use of cannabis for medicinal purposes, a more careful assessment of the possible impacts on embryonic development becomes necessary. Surveys indicate that approximately 3.9% of pregnant women use cannabis in a recreational and/or medicinal manner. However, although the literature has already described the presence of endocannabinoid system components since the early stages of CNS development, many of their physiological effects during this stage have not yet been established. Moreover, it is still uncertain how the endocannabinoid system can be altered in terms of cell proliferation and cell fate, neural migration, neural differentiation, synaptogenesis and particularly cell death. In relation to cell death in the CNS, knowledge about the effects of cannabinoids is scarce. Thus, the present work aims to review the role of the endocannabinoid system in different aspects of CNS development and discuss possible side effects or even opportunities for treating some conditions in the development of this tissue.

Assuntos

Canabinoides , Cannabis , Gravidez , Feminino , Humanos , Canabinoides/farmacologia , Endocanabinoides/metabolismo , Cannabis/metabolismo , Convulsões/induzido quimicamente , Proliferação de Células

RESUMO

The existence of a formal Endocannabinoid System in C. elegans has been questioned due to data showing the absence of typical cannabinoid receptors in the worm; however, the presence of a full metabolism for endocannabinoids, alternative ligands, and receptors for these agents and a considerable number of orthologous and homologous genes regulating physiological cannabinoid-like signals and responses - several of which are similar to those of mammals - demonstrates a well-structured and functional complex system in nematodes. In this review, we describe and compare similarities and differences between the Endocannabinoid System in mammals and nematodes, highlighting the basis for the integral study of this novel system in the worm.

Assuntos

Canabinoides , Endocanabinoides , Animais , Caenorhabditis elegans/metabolismo , Receptores de Canabinoides/metabolismo , Mamíferos/metabolismo

RESUMO

The transient receptor potential vanilloid type-1 (TRPV1) channels have been implicated in the modulation of aversive responses. The endocannabinoid anandamide acts as an endogenous TRPV1 agonist, exerting opposite functions at TRPV1 and type-1 cannabinoid receptors (CB1R). Here we tested the hypothesis that hippocampal TRPV1 modulates contextual fear memory retrieval and investigated the influence of the aversive stimulus intensity as well as the role of endocannabinoid signaling. Male C57BL/6J mice were tested for contextual fear memory after low-, moderate-, or high-intensity shock protocols. The selective TRPV1 blockers SB366791 (1-10 nmol) and 6-I-NC (2 nmol) were infused via intra-dorsal hippocampus before the retrieval test session. The local levels of endocannabinoids and Arc and Zif268 mRNAs, involved in synaptic plasticity and memory, were quantified. First, both TRPV1 blockers reduced memory retrieval in animals exposed to moderate or high (but not low) intensity training protocols. In the second series of results, the magnitude of the freezing responses positively correlated with the hippocampal anandamide levels; TRPV1 and CB1R were found co-localized in this brain region; and the CB1R antagonist, AM251, prevented the effects of SB366791. Thus, endocannabinoid signaling possibly mediates the effects of TRPV1 blockers. Finally, inhibition of memory retrieval by TRPV1 blockers increased Arc and Zif268 mRNAs and impaired fear memory reinstatement. In conclusion, the modulation of fear memories by dorsal hippocampal TRPV1 channels may depend on the aversive stimulus intensity and occur via anandamide/CB1 signaling. Moreover, TRPV1 blockers promote Arc and Zif268 transcription, with subsequent attenuation of aversive memory reinstatement.

Assuntos

Endocanabinoides , Medo , Camundongos , Animais , Masculino , Endocanabinoides/farmacologia , Camundongos Endogâmicos C57BL , Hipocampo , Receptor CB1 de Canabinoide , Canais de Cátion TRPV/metabolismo

RESUMO

ABSTRACT Objective To verify the involvement of the endocannabinoid system in the immunomodulatory profile of stem cells from human exfoliated deciduous teeth, in the presence or absence of TNF-α, and agonist and antagonists of CB1 and CB2. Methods Stem cells from human exfoliated deciduous teeth were cultured in the presence or absence of an agonist, anandamide, and two antagonists, AM251 and SR144528, of CB1 and CB2 receptors, with or without TNF-α stimulation. For analysis of immunomodulation, surface molecules linked to immunomodulation, namely human leukocyte antigen-DR isotype (HLA-DR), and programmed death ligands 1 (PD-L1) and 2 (PD-L2) were measured using flow cytometry. Results The inhibition of endocannabinoid receptors together with the proinflammatory effect of TNF-α resulted in increased HLA-DR expression in stem cells from human exfoliated deciduous teeth, as well as, in these cells acquiring an anti-inflammatory profile by enhancing the expression of PD-L1 and PD-L2. Conclusion Stem cells from human exfoliated deciduous teeth respond to the endocannabinoid system and TNF-α by altering key immune response molecules.

RESUMO

ABSTRACT BACKGROUND AND OBJECTIVES: Faced with the difficulty of treating chronic orofacial pain and seeking an approach that aims at the health and well-being of the patient in a broader way, cannabinoid therapy appears as an adjunct to pharmacological approaches. CONTENTS: Cannabinoid therapy generates analgesia through the activation of the endocannabinoid system, as well as the use of palmitoylethanolamide (PEA), curcumin, grape seed extract, aromatherapy, acupuncture, laser therapy and the practice of physical exercise. In this way, these therapies allow a reduction in the use of analgesic drugs. CONCLUSION: Cannabinoid therapy is part of this integrative approach and the combination of cannabinoids with other forms of activation of the endocannabinoid system contributes to a better therapeutic outcome and a better quality of life for countless patients suffering from chronic orofacial pain.

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RESUMO JUSTIFICATIVA E OBJETIVOS: Diante da dificuldade de tratamento das dores orofaciais crônicas e buscando uma abordagem que vise a saúde e o bem-estar do paciente de uma forma mais ampla, surge a terapia canabinoide como coadjuvante nas abordagens farmacológicas. CONTEÚDO: A terapia canabinoide promove analgesia através da ativação do sistema endocanabinoide, assim como o uso da palmitoiletanolamida (PEA), curcumina, extrato de semente de uva, aromaterapia, acupuntura, laserterapia e a prática de exercício físico. Desta forma, essas terapias permitem redução do uso de fármacos analgésicos. CONCLUSÃO: A terapia canabinoide faz parte dessa abordagem integrativa e a combinação dos canabinoides com outras formas de ativação do sistema endocanabinoide contribui para melhores resultados terapêuticos e melhor qualidade de vida para inúmeros pacientes que sofrem de dores orofaciais crônicas.