RESUMO
The Endocannabinoid System (ECS, also known as Endocannabinoidome) plays a key role in the function of the Central Nervous System, though the participation of this system on the early development - specifically in neuroprotection and proliferation of nerve cells - has been poorly studied. Here, we collect and describe evidence regarding how cannabinoid receptors CB1R and CB2R regulate several cell markers related to proliferation. While CB1R participates in the modulation of neuronal and glial proliferation, CB2R is involved in the proliferation of glial cells. The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) exert significant effects on nerve cell proliferation. AEA generated during embryogenesis induces major effects on the differentiation of neuronal progenitor cells, whereas 2-AG participates in modulating cell migration events rather than affecting the neural proliferation rate. However, although the ECS has been demonstrated to participate in neuroprotection, more characterization on its role in neuronal and glial proliferation and differentiation is needed, especially in brain areas with recognized high neurogenesis rates. This has encouraged scientists to elucidate and propose specific mechanisms related with these cell proliferation mechanisms to better understand some neurodegenerative disorders such as Parkinson, Huntington and Alzheimer diseases, in which neuronal loss and poor neurogenesis are crucial factors for their onset and progression. In this review, we collect and present recent evidence published pointing to an active role of the ECS in the development and proliferation of nerve cells.
Assuntos
Sistema Nervoso Central , Endocanabinoides , Receptores de Canabinoides/fisiologia , Neurônios , Proliferação de CélulasRESUMO
The participation of the peripheral opioid and cannabinoid endogenous systems in modulating muscle pain and inflammation has not been fully explored. Thus, the aim of this study was to investigate the involvement of these endogenous systems during muscular-tissue hyperalgesia induced by inflammation. Hyperalgesia was induced by carrageenan injection into the tibialis anterior muscles of male Wistar rats. We padronized an available Randal-Sellito test adaptation to evaluate nociceptive behavior elicited by mechanical insult in muscles. Western blot analysis was performed to evaluate the expression levels of opioid and cannabinoid receptors in the dorsal root ganglia. The non-selective opioid peptide receptor antagonist (naloxone) and the selective mu opioid receptor MOP (clocinnamox) and kappa opioid receptor KOP (nor-binaltorphimine) antagonists were able to intensify carrageenan-induced muscular hyperalgesia. On the other hand, the selective delta opioid receptor (DOP) antagonist (naltrindole) did not present any effect on nociceptive behavior. Moreover, the selective inhibitor of aminopeptidases (Bestatin) provoked considerable dose-dependent analgesia when intramuscularly injected into the hyperalgesic muscle. The CB1 receptor antagonist (AM251), but not the CB2 receptor antagonist (AM630), intensified muscle hyperalgesia. All irreversible inhibitors of anandamide hydrolase (MAFP), the inhibitor for monoacylglycerol lipase (JZL184) and the anandamide reuptake inhibitor (VDM11) decreased carrageenan-induced hyperalgesia in muscular tissue. Lastly, MOP, KOP and CB1 expression levels in DRG were baseline even after muscular injection with carrageenan. The endogenous opioid and cannabinoid systems participate in peripheral muscle pain control through the activation of MOP, KOP and CB1 receptors.
Assuntos
Mialgia/tratamento farmacológico , Receptores de Canabinoides/fisiologia , Receptores Opioides/fisiologia , Animais , Ácidos Araquidônicos/antagonistas & inibidores , Carragenina , Cinamatos/farmacologia , Endocanabinoides/antagonistas & inibidores , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/psicologia , Masculino , Monoacilglicerol Lipases/antagonistas & inibidores , Derivados da Morfina/farmacologia , Mialgia/induzido quimicamente , Mialgia/psicologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Medição da Dor/efeitos dos fármacos , Alcamidas Poli-Insaturadas/antagonistas & inibidores , Ratos , Ratos Wistar , Receptores de Canabinoides/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Receptores Opioides delta/efeitos dos fármacos , Receptores Opioides kappa/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacosRESUMO
RATIONALE: Prepulse inhibition of the startle reflex (PPI) is disrupted in several psychiatric disorders including schizophrenia. Understanding PPI pharmacology may help elucidate the pathophysiology of these disorders and lead to better treatments. Given the advantages of multi-target approaches for complex mental illnesses treatment, we have investigated the interaction between receptors known to modulate PPI (5-HT1A and 5-HT2A) and the neuromodulatory endocannabinoid system. OBJECTIVES: To investigate serotonin and cannabinoid receptor (CBR) co-modulation in a model of PPI disruption relevant to schizophrenia METHODS: Male Swiss mice were pretreated with WIN 55,212-2 (CBR agonist), rimonabant (CB1R inverse agonist), 8-OH-DPAT (5-HT1A/7 agonist), and volinanserin (5-HT2A antagonist) or with a combination of a cannabinoid and a serotonergic drug. PPI disruption was induced by acute administration of MK-801. RESULTS: WIN 55,212-2 and rimonabant did not change PPI nor block MK-801-induced deficits. 8-OH-DPAT increased PPI in control mice and, in a higher dose, inhibited MK-801-induced impairments. Volinanserin also increased PPI in control and MK-801-treated mice, presenting an inverted U-shaped dose-response curve. Co-administration of either cannabinoid ligand with 8-OH-DPAT did not change PPI; however, the combination of volinanserin with rimonabant increased PPI in both control and MK-801-exposed mice. CONCLUSIONS: WIN 55,212-2 and rimonabant had similar effects in PPI. Moreover, serotonin and cannabinoid receptors interact to modulate PPI. While co-modulation of CBR and 5-HT1A receptors did not change PPI, a beneficial effect of 5-HT2A and CB1R antagonist combination was detected, possibly mediated through potentiation of 5-HT2A blockade effects by concomitant CB1R blockade.
Assuntos
Antagonistas de Receptores de Canabinoides/administração & dosagem , Inibição Pré-Pulso/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptores de Canabinoides/fisiologia , Esquizofrenia/tratamento farmacológico , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Animais , Benzoxazinas/administração & dosagem , Moduladores de Receptores de Canabinoides/administração & dosagem , Canabinoides/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Fluorbenzenos/administração & dosagem , Masculino , Camundongos , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Piperidinas/administração & dosagem , Inibição Pré-Pulso/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Resultado do TratamentoRESUMO
The endocannabinoid system participates in the regulation of CNS homeostasis and functions, including neurotransmission, cell signaling, inflammation and oxidative stress, as well as neuronal and glial cell proliferation, differentiation, migration and survival. Endocannabinoids are produced by multiple cell types within the CNS and their main receptors, CB1 and CB2, are expressed in both neurons and glia. Signaling through these receptors is implicated in the modulation of neuronal and glial alterations in neuroinflammatory, neurodegenerative and psychiatric conditions, including Alzheimer's, Parkinson's and Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, epilepsy, anxiety and depression. The therapeutic potential of endocannabinoid receptors in neurological disease has been hindered by unwelcome side effects of current drugs used to target them; however, due to their extensive expression within the CNS and their involvement in physiological and pathological process in nervous tissue, they are attractive targets for drug development. The present review highlights the potential applications of the endocannabinoid system for the prevention and treatment of neurologic and psychiatric disorders.
Assuntos
Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/prevenção & controle , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/prevenção & controle , Receptores de Canabinoides/efeitos dos fármacos , Receptores de Canabinoides/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Moduladores de Receptores de Canabinoides/fisiologia , Endocanabinoides , Humanos , Inflamação/metabolismo , Transtornos Mentais/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Plasticidade Neuronal/fisiologia , Neurônios/metabolismoRESUMO
Described during the late 1980s and 1990s, cannabinoid receptors (CB1R and CB2R) are G-protein-coupled receptors (GPCRs) activated by endogenous ligands and cannabinoid drug compounds, such as Δ9-THC. Whereas CB1R has a role in the regulation of neurotransmission in different brain regions and mainly mediates the psychoactive effects of cannabinoids, CB2R is found predominantly in the cells and tissues of the immune system and mediates anti-inflammatory and immunomodulatory processes. Studies have demonstrated that CB1R and CB2R can affect the activation of T cells, B cells, monocytes, and microglial cells, inhibiting proinflammatory cytokine expression and upregulating proresolution mediators. Thus, in this review, we summarize the mechanisms by which CBRs interact with the autoimmune environment and the potential to suppress the development and activation of autoreactive cells. Finally, we highlight how the modulation of CB1R and CB2R is advantageous in the treatment of autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes mellitus (T1DM) and rheumatoid arthritis (RA).
Assuntos
Doenças Autoimunes/tratamento farmacológico , Moduladores de Receptores de Canabinoides/uso terapêutico , Receptores de Canabinoides/fisiologia , Animais , Anti-Inflamatórios , Artrite Reumatoide , Diabetes Mellitus Tipo 1 , Humanos , Ligantes , Esclerose MúltiplaRESUMO
Endocannabinoids are ancient biomolecules involved in several cellular (e.g., metabolism) and physiological (e.g., eating behaviour) functions. Indeed, eating behaviour alterations in marijuana users have led to investigate the orexigenic/anorexigenic effects of cannabinoids in animal/ human models. This increasing body of research suggests that the endocannabinoid system plays an important role in feeding control. Accordingly, within the endocannabinoid system, cannabinoid receptors, enzymes and genes represent potential therapeutic targets for dealing with multiple metabolic and behavioural dysfunctions (e.g., obesity, anorexia, etc.). Paradoxically, our understanding on the endocannabinoid system as a cellular mediator is yet limited. For example: (i) only two cannabinoid receptors have been classified, but they are not enough to explain the pharmacological profile of several experimental effects induced by cannabinoids; and (ii) several orphan G protein-coupled receptors (GPCRs) interact with cannabinoids and we do not know how to classify them (e.g., GPR18, GPR55 and GPR119; amongst others). On this basis, the present review attempts to summarize the lines of evidence supporting the potential role of GPR18, GPR55 and GPR119 in metabolism and feeding control that may explain some of the divergent effects and puzzling data related to cannabinoid research. Moreover, their therapeutic potential in feeding behaviour alterations will be considered.
Assuntos
Endocanabinoides/metabolismo , Endocanabinoides/farmacologia , Receptores de Canabinoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Canabinoides , Endocanabinoides/química , Endocanabinoides/fisiologia , Humanos , Receptores de Canabinoides/fisiologia , Receptores Acoplados a Proteínas G/fisiologiaRESUMO
2-Arachidonoylglycerol (2-AG) is one of the principal endocannabinoids involved in the protection against neurodegenerative processes. Cannabinoids primarily interact with the seven-segment transmembrane cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), both of which are expressed in the central nervous system (CNS). The level of 2-AG is controlled through key enzymes responsible for its synthesis or degradation. We have previously observed a deregulation of 2-AG metabolism in physiological aging. The aim of this study was to analyze how 2-AG metabolism is modulated by CB1/CB2 receptors during aging. To this end, both CB1 and CB2 receptor expression and the enzymatic activities (diacylglycerol lipase (DAGL), lysophosphatidate phosphohydrolase (LPAase) and monoacylglycerol lipase (MAGL)) involved in 2-AG metabolism were analyzed in the presence of cannabinoid receptor (CBR) agonists (WIN and JWH) and/or antagonists (SR1 and SR2) in synaptosomes from adult and aged rat cerebral cortex (CC). Our results demonstrate that: (a) aging decreases the expression of both CBRs; (b) LPAase inhibition, due to the individual action of SR1 or SR2, is reverted in the presence of both antagonists together; (c) LPAase activity is regulated mainly by the CB1 receptor in adult and in aged synaptosomes while the CB2 receptor acquires importance when CB1 is blocked; (d) modulation via CBRs of DAGL and MAGL by both antagonists occurs only in aged synaptosomes, stimulating DAGL and inhibiting MAGL activities; (e) only DAGL stimulation is reverted by WIN. Taken together, the results of the present study show that CB1 and/or CB2 receptor antagonists trigger a significant modulation of 2-AG metabolism, underlining their relevance as therapeutic strategy for controlling endocannabinoid levels in physiological aging.
Assuntos
Envelhecimento/metabolismo , Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Receptores de Canabinoides/fisiologia , Animais , Membrana Celular/metabolismo , Córtex Cerebral/metabolismo , Lipase Lipoproteica/metabolismo , Monoacilglicerol Lipases/metabolismo , Fosfatidato Fosfatase/metabolismo , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo , Receptores de Canabinoides/metabolismo , Sinaptossomos/metabolismoRESUMO
Endocannabinoids (ECBs) are ubiquitous lipophilic agents, and this characteristic is consistent with the wide range of homeostatic functions attributed to the ECB system. There is an increasing number of studies showing that the ECB system affects neurotransmission within the hypothalamic neurohypophyseal system. We provide an overview of the primary roles of ECBs in the modulation of neuroendocrine function and, specifically, in the control of hydromineral homeostasis. Accordingly, the general aspects of ECB-mediated signalling, as well as the specific contributions of the central component of the ECB system to the integration of behavioural and endocrine responses that control body fluid homeostasis, are discussed.
Assuntos
Endocanabinoides/fisiologia , Minerais/metabolismo , Sistemas Neurossecretores/fisiologia , Equilíbrio Hidroeletrolítico/fisiologia , Animais , Humanos , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptores de Canabinoides/fisiologiaRESUMO
The dramatic increase in the prevalence of obesity worldwide represents one of the most important challenges of modern medicine, owing to its myriad related complications-in particular cardiovascular disease, the leading cause of death worldwide. Originating from early studies with Cannabis sativa, the active compound of marijuana, there has been an impressive progress in the knowledge about the endocannabinoid network, leading to the identification of specific pathways that modulate feeding behavior. The effects of endocannabinoids are not limited to the central nervous system, but also include peripheral tissues. Experimental and clinic trials have demonstrated the efficacy of endocannabinoid antagonists in the management of obesity and the cardiometabolic syndrome. Better understanding of the mechanisms underlying obesity will lead to development of more active and specific agents, which surely will enlarge the role of this efficacious alternative for management of obesity.
Assuntos
Moduladores de Receptores de Canabinoides/fisiologia , Endocanabinoides , Receptores de Canabinoides/fisiologia , Humanos , Síndrome Metabólica/tratamento farmacológico , Vias Neurais/fisiologia , Obesidade/tratamento farmacológico , Receptores de Canabinoides/efeitos dos fármacosRESUMO
Despite the public concern about the controversial use and abuse of marijuana, the scientific community has focused on the therapeutic potentials of cannabinoid compounds and had highlighted the importance of endocannabinoids and their receptors in physiology and disease. Endocannabinoids have been shown to be important mediators in neuroendocrine and psychiatric processes such as food intake, drug reward and energy metabolism. Cannabinoid receptors are expressed by several cell lines in the liver, such as hepatocytes, myofibroblastic cells, endothelial cells and probably cholangiocytes. A perpetuating role in liver damage for the endocannabinoid system has been proposed in several steps of chronic liver disease progression. Being a major cause of death worldwide, chronic liver disease is an important problem. New therapies are needed in order to stop or slow damage progression. This review summarizes the results of experimental studies involving the endocannabinoid system in liver disease and their clinical and therapeutical implications in hepatology.