RESUMO
Molecular engineering of drug delivering platforms to provide collaborative biological effects with loaded drugs is of great medical significance. Herein, cannabinoid receptor 1 (CB1)- and reactive oxygen species (ROS)-targeting electrosprayed microspheres (MSs) are fabricated by loading with the CB1 agonist arachidonoyl 2'-chloroethylamide (ACEA) and producing ROS in a photoresponsive manner. The synergistic anti-tumor effects of ACEA and ROS released from the MSs are assessed. ACEA inhibits epidermal growth factor receptor signaling and altered tumor microenvironment (TME) by activating CB1 to induce tumor cell death. The MSs are composed of glycidyl methacrylate-conjugated xanthan gum (XGMA) and Fe3+, which form dual molecular networks based on a Fe3+-(COO-)3 network and a CâC addition reaction network. Interestingly, the Fe3+-(COO-)3 network can be disassembled instantly under the conditions of lactate sodium and ultraviolet exposure, and the disassembly is accompanied by massive ROS production, which directly injures tumor cells. Meanwhile, the transition of dual networks to a single network boosts the ACEA release. Together, the activities of the ACEA and MSs promote immunogenic tumor cell death and create a tumor-suppressive TME by increasing M1-like tumor-associated macrophages and CD8+ T cells. In summation, this study demonstrates strong prospects of improving anti-tumor effects of drug delivering platforms through molecular design.
Assuntos
Antineoplásicos , Ácidos Araquidônicos , Agonistas de Receptores de Canabinoides , Neoplasias Colorretais , Imunoterapia , Receptor CB1 de Canabinoide , Microambiente Tumoral , Hidrogéis/administração & dosagem , Microesferas , Imunoterapia/métodos , Receptor CB1 de Canabinoide/agonistas , Espécies Reativas de Oxigênio/metabolismo , Agonistas de Receptores de Canabinoides/administração & dosagem , Agonistas de Receptores de Canabinoides/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Sistemas de Liberação de Medicamentos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Humanos , Linhagem Celular Tumoral , Raios Ultravioleta , Ácidos Araquidônicos/administração & dosagem , Ácidos Araquidônicos/farmacologia , Polissacarídeos Bacterianos/química , Compostos de Epóxi/química , Metacrilatos/química , Desenho de FármacosRESUMO
Some studies suggest that the effect of cannabis on behavior performance depends on the presence of ovarian hormones and the age of use initiation. Estradiol is the main ovarian hormone that can interact with cannabinoids. It has been suggested that cannabinoids exert some of their effects directly through estrogen receptors (ERs). A novel G-protein-coupled receptor (GPR30) was described as mediating estrogen signaling in various cell lines. Since there are few studies on the interaction of cannabis and ovarian hormones on cognitive behaviors, so, this study evaluated the role of GPR30 in the effects of marijuana (M) and estrogen, alone and in combination, on spatial learning and memory of young (non-ovarian(OVX)) and old female rats. Young (5-7 months) and old (22-24 months) female rats received an intraperitoneal injection (i.p) of 17ß-estradiol (E2), G1 (GPR30 agonist), and G15 (GPR30 antagonist) every four days, and M (every day), either alone or in combination, for 28 days. One hour after the last injection, the Morris water maze (MWM) test was conducted to evaluate of spatial learning and memory. Moreover, hippocampal BDNF level was assessed by the ELISA method. The results showed a positive effect of M on spatial learning in both young and old rats, however, E2 showed beneficial effects on the memory of young, but not old rats. Our results showed that GPR30 does not have any role in the interaction effects of M and E2 in young rats. Although both E2 and M alone showed positive effects on spatial learning and memory in old rats, however, our results showed a negative interaction between marijuana and E2 combined effects on spatial learning and memory in old female rats which is mediated by GPR30. Our results showed that the effects of GPR30 on spatial learning and memory is age dependent. Furthermore, this study showed that hippocampal BDNF does not have any role in the interaction effects of M and E2 on spatial learning and memory in young and old rats.
Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Estradiol/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Aprendizagem Espacial/efeitos dos fármacos , Fatores Etários , Animais , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Agonistas de Receptores de Canabinoides/administração & dosagem , Interações Medicamentosas , Estradiol/administração & dosagem , Hipocampo/metabolismo , Ratos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidoresRESUMO
Increasing evidence shows the interaction effect of cannabinoids and sleep on cognitive functions. In the present study, we aimed to investigate the interaction effect of cannabinoids type 1 receptor (CB1r) in the CA1 hippocampal region and sleep deprivation (SD) on passive avoidance memory and depressive-like behavior in male Wistar rats. We used water box apparatus to induce total SD (TSD) for 24 h. The shuttle-box was applied to assess passive avoidance memory and locomotion apparatus was applied to assess locomotor activity. Forced swim test (FST) was used to evaluate rat's behavior. ACPA (CB1r agonist) at the doses of 0.01, 0.001 and 0.0001 µg/rat, and AM251 (CB1r antagonist) at the doses of 100, 10 and 1 ng/rat were injected intra-CA1, five minutes after training via stereotaxic surgery. Results showed SD impaired memory. ACPA at the doses of 0.01 and 0.001 µg/rat impaired memory and at all doses did not alter the effect of SD on memory. AM251 by itself did not alter memory, while at lowest dose (1 ng/rat) restored SD-induced memory deficit. Both drugs induced depressive-like behavior in a dose-dependent manner. Furthermore, both drugs decreased swimming at some doses (ACPA at 0.0001 µg/rat, AM251 at 0.001 and 0.01 ng/rat). Also, ACPA at the highest dose increased climbing of SD rats. In conclusion, we suggest CB1r may interact with the effect of SD on memory. Additionally, cannabinoids may show a dose-dependent manner in modulating mood and behavior. Interestingly, CB1r agonists and antagonists may exhibit a similar effect in some behavioral assessments.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Região CA1 Hipocampal , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Depressão , Locomoção/efeitos dos fármacos , Transtornos da Memória , Receptor CB1 de Canabinoide/metabolismo , Privação do Sono , Animais , Ácidos Araquidônicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Agonistas de Receptores de Canabinoides/administração & dosagem , Antagonistas de Receptores de Canabinoides/administração & dosagem , Depressão/induzido quimicamente , Depressão/metabolismo , Depressão/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Privação do Sono/complicações , Privação do Sono/metabolismo , NataçãoRESUMO
OBJECTIVE: The members of the matrix metalloproteinase (MMP) family and cannabinoids (CBs) are reportedly associated with hippocampus-dependent memory functions. However, the effects of endogenously formed CBs on hippocampal long-term potentiation remain unknown. The present study aimed to investigate the changes in the gene and protein expression levels of matrix metallopeptidase 9 (MMP-9), phosphatase and tensin homolog (PTEN), and NOTCH receptor 1 (NOTCH1) in rat hippocampal tissues treated with anandamide (AEA), AM251, 6-iodopravadolin (AM630), and N-[4-{[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl}phenyl] (ML193). MATERIALS AND METHODS: The subjects were divided into 10 groups (n = five per group). The pharmaceuticals were administered via intraperitoneal injection once a day for seven days, except for the control group. The resected hippocampal tissues were then evaluated using a quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analysis. The data obtained were statistically analyzed, and p < 0.01 was considered statistically significant. RESULTS: Contrary to the literature, the changes in MMP-9 expression were not statistically significant, but the changes in PTEN and NOTCH1 were. The findings of this in vivo experimental study revealed that the agonists and antagonists acting on the CB system have significant molecular effects on hippocampal tissue. CONCLUSIONS: The changes in gene and protein expressions may be one of the reasons for the neurodegenerative processes observed in patients using these agonists and antagonists, whose effects on the CB system have not been fully explained yet. Our study can contribute to the literature as it is the first study investigating the MMP-9, PTEN and NOTCH1 gene and protein expression.
Assuntos
Ácidos Araquidônicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Endocanabinoides/farmacologia , Hipocampo/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Animais , Ácidos Araquidônicos/administração & dosagem , Agonistas de Receptores de Canabinoides/administração & dosagem , Método Duplo-Cego , Endocanabinoides/administração & dosagem , Hipocampo/metabolismo , Injeções Intraperitoneais , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , PTEN Fosfo-Hidrolase/genética , Alcamidas Poli-Insaturadas/administração & dosagem , Ratos , Ratos Wistar , Receptor Notch1/genéticaRESUMO
Electronic cigarettes (e-cigarettes) are noncombustible tobacco products that have been promoted as safer alternatives to conventional cigarettes and beneficial tools for smoking cessation. However, e-cigarettes have been shown to produce aerosols with high concentrations of propylene glycol, glycerol, volatile organic compounds, and free radicals, which can lead to lung damage. Furthermore, e-cigarettes can deliver nicotine at concentrations higher than traditional combustibles, making them highly addictive. As delivery devices became smaller, less expensive, and refillable, the use of e-cigarettes dramatically increased, especially among adolescents and young adults in the United States. This rise in popularity of noncombustible products led to an outbreak of e-cigarette or vaping product use-associated lung injury (EVALI) in the fall of 2019. In this article, we review the history of e-cigarettes and its prevalence among American youth, the EVALI outbreak and clinical presentation of EVALI patients, and recent legislative efforts to regulate e-cigarette use.
Assuntos
Lesão Pulmonar Aguda/epidemiologia , Vaping/epidemiologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/fisiopatologia , Adolescente , Canabidiol/administração & dosagem , Agonistas de Receptores de Canabinoides/administração & dosagem , Criança , Surtos de Doenças , Dronabinol/administração & dosagem , Vapor do Cigarro Eletrônico/efeitos adversos , Vapor do Cigarro Eletrônico/química , Sistemas Eletrônicos de Liberação de Nicotina , Humanos , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Estados Unidos/epidemiologia , Vaping/efeitos adversos , Vaping/legislação & jurisprudência , Adulto JovemRESUMO
INTRODUCTION: Tobacco use disorder (TUD) is a chronic relapsing condition. Existing pharmacotherapy can assist smokers to initiate smoking cessation, but relapse rates remain high. Novel therapeutics are required to help people quit and also to prevent relapse. The endocannabinoid system has been increasingly implicated in reward and addiction processes and the cannabinoid CB1 receptor inverse agonist rimonabant has been shown to be effective at promoting smoking cessation but has been associated with adverse psychiatric side effects. AREAS COVERED: Multiple converging factors likely contribute to the maintenance of smoking and cause relapse including nicotine reinforcement, propensity to reinstate drug seeking (induced by nicotine priming, nicotine-associated cues, and stress), the severity of withdrawal signs and executive function status. Studies assessing the impact of endocannabinoid (CB1 receptor, CB2 receptor, anandamide, and 2-arachidonoylglycerol) modulation on these addiction-related factors are reviewed. Future research avenues are also discussed. EXPERT OPINION: Endocannabinoid research in TUD is at a relatively early stage. Based on current evidence, CB1 receptor neutral antagonists and fatty acid amide hydrolase inhibitors demonstrate positive effects in studies assessing several addiction-related factors. This suggests they offer the greatest promise as novel cessation and anti-relapse agents.
Assuntos
Desenvolvimento de Medicamentos , Endocanabinoides/metabolismo , Tabagismo/tratamento farmacológico , Animais , Agonistas de Receptores de Canabinoides/administração & dosagem , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/administração & dosagem , Antagonistas de Receptores de Canabinoides/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Humanos , Abandono do Hábito de Fumar/métodos , Tabagismo/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVE: ∆9-Tetrahydrocannabinol (THC) exhibits several therapeutic effects, such as analgesics, anti-emetic, antispastic, and muscle relaxation properties. Knowledge concerning THC disposition in target organs is crucial for THC therapy. The objective of this study was to develop a physiologically-based pharmacokinetic (PBPK) model of THC in humans to characterize tissue-specific pharmacokinetics of THC in organs of interest. METHODS: The model was extrapolated from the previously developed PBPK model conducted in mice, rats, and pigs. The model consisted of seven compartments: brain, lungs, liver, kidneys, fat, and rapidly perfused and slowly perfused tissues. P-glycoprotein was included in the brain compartment to characterize an efflux of THC from the brain. Physiologic, biochemical, and physicochemical parameters were determined and acquired from the literature. Model validation was performed by comparisons of the predicted and observed THC concentrations acquired from published studies. RESULTS: The developed PBPK model resulted in good agreement between the predicted and observed THC concentrations across several studies conducted following IV bolus, IV infusion, oral, and smoking and inhalation, with the coefficient of determination (R2) ranging from 0.54 to 0.95. CONCLUSIONS: A PBPK model of THC in humans was developed. The model could describe THC concentration-time profiles in several dosing scenarios (i.e., IV bolus, IV infusion, oral administration and inhalation).
Assuntos
Agonistas de Receptores de Canabinoides/farmacocinética , Dronabinol/farmacocinética , Modelos Biológicos , Administração por Inalação , Administração Oral , Adolescente , Adulto , Disponibilidade Biológica , Agonistas de Receptores de Canabinoides/administração & dosagem , Dronabinol/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Distribuição Tecidual , Adulto JovemRESUMO
The rapid proliferation of new synthetic cannabinoid receptor agonists (SCRAs) has initiated considerable interest in the development of so-called "untargeted" screening strategies. One of these new screening technologies involves the activity-based detection of SCRAs. In this study, we evaluated whether (synthetic) cannabinoid activity can be detected in oral fluid (OF) and, if so, whether it correlates with SCRA concentrations. OF was collected at several time points in a placebo-controlled JWH-018 administration study. The outcome of the cell-based cannabinoid reporter system, which monitored the cannabinoid receptor activation, was compared to the quantitative data for JWH-018, obtained via a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. A total of 175 OF samples were collected and analyzed via both methods. The cannabinoid reporter assay correctly classified the vast majority of the samples as either negative (<0.25 ng/mL; 74/75 = 99%) or having low (0.25-1.5 ng/mL; 16/16 = 100% and 1.5-10 ng/mL; 37/41 = 90%), mid (10-100 ng/mL; 23/25 = 92%) or high (>100 ng/mL; 16/18 = 89%) JWH-018 concentrations. Passing-Bablok regression analysis yielded a good linear correlation, with no proportional difference between both methods (slope 0.97; 95% confidence interval 0.86-1.14) and only a small systematic difference. This is the first study to demonstrate the applicability of an untargeted, activity-based approach for SCRA detection in OF. Additionally, the outcome of the cannabinoid reporter assay was compared to the gold standard (LC-MS/MS), showing a good correlation between both methods, indicating that the cannabinoid reporter assay can be used for an estimation of drug concentrations.
Assuntos
Líquidos Corporais/química , Agonistas de Receptores de Canabinoides/análise , Indóis/análise , Naftalenos/análise , Administração por Inalação , Agonistas de Receptores de Canabinoides/administração & dosagem , Cromatografia Líquida , Estudos Cross-Over , Humanos , Indóis/administração & dosagem , Naftalenos/administração & dosagem , Espectrometria de Massas em Tandem , VapingRESUMO
CD8+ T cells can contribute to neuroinflammation by secretion of inflammatory cytokines like interferon γ (IFNγ) and tumor necrosis factor α (TNFα). Astrocytes, a glial cell in the brain, can be stimulated by IFNγ and TNFα to secrete the inflammatory cytokines, monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), and interferon-γ inducible protein 10 (IP-10). Δ9-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in Cannabis sativa, possesses potent anti-inflammatory activity. The objective of this investigation was to assess the effects of THC treatment on CD8+ T cell-mediated activation of astrocytes. CD3/CD28/IFNα- stimulated CD8+ T cells were treated with vehicle (0.03% EtOH) or THC and cocultured with U251 astrocytes. IP-10+, MCP-1+, and IL-6+ astrocytes were quantified by flow cytometry. LegendPlex™ was used to measure cytokine secretion by CD8+ T cells and flow cytometry was employed to quantify IFNγ, TNFα, and lysosomal-associated membrane protein 1 (LAMP-1) expression. Recombinant TNFα and IFNγ were used to stimulate MCP-1, IP-10, IL-6 responses in U251 astrocytes, which were measured by flow cytometry. Treatment with THC reduced CD8+ T cell-mediated induction of IP-10 and IL-6 responses in U251 astrocytes but had no effect on MCP-1. THC treatment differentially affected T cell effector functions such that IFNγ and degranulation responses were sensitive to THC-mediated ablation while TNFα was not. Lastly, THC treatment reduced the IFNγ-induced IP-10 response but had no effect on TNFα-induced MCP-1 response in U251 astrocytes. The results suggest that cannabinoid treatment can selectively reduce certain CD8+ T cell responses that contribute to stimulation of astrocytes. Graphical Abstract Treatment with THC can abate CD8+ T cell-dependent neuroinflammatory processes by inhibiting CD8+ cell differentiation into effector cells, suppressing CD8+ effector cell function, and reducing activation of astrocytes by CD8+ T cell-derived inflammatory cytokines.
Assuntos
Astrócitos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/administração & dosagem , Dronabinol/administração & dosagem , Astrócitos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Técnicas de Cocultura , Relação Dose-Resposta a Droga , HumanosRESUMO
The aim of this study was to evaluate the effect of palmitoylethanolamide (PEA), a cannabimimetic compound and lipid messenger, on recovery from muscle damaging exercise. Twenty-eight healthy young male participants attended the laboratory four times on subsequent days. In the first visit, baseline characteristics were recorded before participants were randomized to consume either liquid PEA (167.5 mg Levagen+ with 832.5 mg maltodextrin) or a matched placebo (1 g maltodextrin) drink. Leg press exercise consisted of four sets at 80% of one repetition maximum followed by a performance set. Muscle soreness, thigh circumference, blood lactate concentration, biomarkers of muscle damage and inflammation, and transcription factor pathways were measured pre- and immediately post-exercise and again at 1, 2, 3, 24, 48, and 72 h post-exercise. The leg press exercise increased (p < 0.05) blood lactate concentration and induced muscle damage as evidenced by increased muscle soreness, thigh circumference, biomarkers of muscle damage, and concentrations of tumor necrosis factor-α. PEA reduced (p < 0.05) myoglobin and blood lactate concentrations and increased protein kinase B phosphorylation following exercise. Taken together, these results indicate PEA supplementation may aid in muscle recovery from repeat bouts of exercise performed within a short duration by reducing myoglobin and lactate concentration.
Assuntos
Amidas/administração & dosagem , Agonistas de Receptores de Canabinoides/administração & dosagem , Etanolaminas/administração & dosagem , Exercício Físico/fisiologia , Músculo Esquelético/efeitos dos fármacos , Mialgia/tratamento farmacológico , Ácidos Palmíticos/administração & dosagem , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Ácido Láctico/sangue , Ácido Láctico/metabolismo , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Mialgia/sangue , Mialgia/etiologia , Mioglobina/sangue , Mioglobina/metabolismo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo , Adulto JovemAssuntos
Transtornos de Ansiedade/tratamento farmacológico , Canabidiol/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Doença de Crohn/tratamento farmacológico , Adolescente , Transtornos de Ansiedade/etiologia , Canabidiol/administração & dosagem , Agonistas de Receptores de Canabinoides/administração & dosagem , Doença de Crohn/complicações , Feminino , HumanosRESUMO
BACKGROUND AND PURPOSE: Adolescents are regularly exposed to ∆9 -tetrahydrocannabinol (THC) via smoking and, more recently, vaping cannabis extracts. Growing legalization of cannabis for medical and recreational purposes, combined with decreasing perceptions of harm, makes it increasingly important to determine the consequences of frequent adolescent exposure for motivated behaviour and lasting tolerance in response to THC. EXPERIMENTAL APPROACHES: Male and female rats inhaled THC vapour, or that from the propylene glycol (PG) vehicle, twice daily for 30 min from postnatal day (PND) 35-39 and PND 42-46 using an e-cigarette system. Thermoregulatory responses to vapour inhalation were assessed by radio-telemetry during adolescence and from PND 86-94. Chow intake was assessed in adulthood. Blood samples were obtained from additional adolescent groups following initial THC inhalation and after 4 days of twice daily exposure. Additional groups exposed repeatedly to THC or PG during adolescence were evaluated for intravenous self-administration of oxycodone as adults. KEY RESULTS: Female, not male, adolescents developed tolerance to the hypothermic effects of THC inhalation in the first week of repeated exposure despite similar plasma THC levels. Each sex exhibited tolerance to THC hypothermia in adulthood after repeated adolescent THC. However, enhanced potency was found in females. Repeated THC male rats consumed more food than their PG-treated control group, without significant bodyweight differences. Adolescent THC did not alter oxycodone self-administration in either sex but increased fentanyl self-administration in females. CONCLUSIONS AND IMPLICATIONS: Repeated THC vapour inhalation in adolescent rats has lasting consequences observable in adulthood.
Assuntos
Dronabinol/administração & dosagem , Sistemas Eletrônicos de Liberação de Nicotina , Alucinógenos/administração & dosagem , Hipotermia/induzido quimicamente , Caracteres Sexuais , Administração por Inalação , Fatores Etários , Analgésicos Opioides/administração & dosagem , Animais , Agonistas de Receptores de Canabinoides/administração & dosagem , Agonistas de Receptores de Canabinoides/sangue , Agonistas de Receptores de Canabinoides/toxicidade , Relação Dose-Resposta a Droga , Dronabinol/sangue , Dronabinol/toxicidade , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Feminino , Alucinógenos/sangue , Alucinógenos/toxicidade , Hipotermia/fisiopatologia , Masculino , Oxicodona/administração & dosagem , Ratos , Ratos Wistar , AutoadministraçãoRESUMO
Bone cancer pain (BCP) is a severe complication of advanced bone cancer. Although cannabinoid receptor 2 (CB2) agonists may have an analgesic effect, the underlying mechanism remains unclear. CB2 serves a protective role in various pathological states through the activation of autophagy. Therefore, the present study aimed to determine whether the analgesic effects of the selective CB2 agonist JWH015 was mediated by the activation of autophagy in BCP. BCP was induced by the intrafemur implantation of NCTC2472 fibrosarcoma cells in C3H/HeN mice. The pain behaviors were assessed on the following postoperative days. The selective CB2 agonist JWH015 (1 and 2 µg) was intrathecally administered on day 14 following implantation. AM630 (1 µg), a CB2 antagonist, was injected 30 min before JWH015 administration. Lipopolysaccharide (LPS; 100 nM)stimulated primary neurons were treated with JWH015 (1 µM) and AM630 (1 µM) to further verify the mechanism by which CB2 affects autophagy. The results demonstrated that autophagy flux was impaired in spinal neurons during BCP, as indicated by the increased ratio of microtubuleassociated protein 1 light chain 3ß (LC3B)II/LC3BI and increased expression of p62. Intrathecal administration of JWH015 attenuated BCP, which was accompanied by the amelioration of impaired autophagy flux (decreased LC3BII/LC3BI ratio and decreased p62expression). In addition, the activation of glia cells and upregulation of the gliaderived inflammatory mediators, interleukin (IL)1ß and IL6 were suppressed by JWH015. In LPSstimulated primary neurons, IL1ß and IL6 were increased, and autophagy flux was impaired; whereas treatment with JWH015 decreased the expression of IL1ß and IL6, LC3BII/LC3BI ratio and expression of p62. These effects were by pretreatment with the CB2selective antagonist AM630. The results of the present study suggested that the impairment of autophagy flux was induced by gliaderived inflammatory mediators in spinal neurons. Intrathecal administration of the selective CB2 agonist JWH015 ameliorated autophagy flux through the downregulation of IL1ß and IL6 and attenuated BCP.
Assuntos
Autofagia/efeitos dos fármacos , Dor do Câncer/metabolismo , Agonistas de Receptores de Canabinoides/farmacologia , Indóis/farmacologia , Mediadores da Inflamação/metabolismo , Manejo da Dor , Receptor CB2 de Canabinoide/metabolismo , Medula Espinal/metabolismo , Animais , Neoplasias Ósseas/complicações , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Agonistas de Receptores de Canabinoides/administração & dosagem , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Indóis/administração & dosagem , Injeções Espinhais , Masculino , Camundongos , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologiaRESUMO
The high prevalence of concomitant cannabis and nicotine use has implications for sensory and cognitive processing. While nicotine tends to enhance function in these domains, cannabis use has been associated with both sensory and cognitive impairments, though the underlying mechanisms are unclear. Additionally, the interaction of the nicotinic (nAChR) and cannabinoid (CB1) receptor systems has received limited study in terms of sensory/cognitive processes. This study involving healthy volunteers assessed the acute separate and combined effects of nabilone (a CB1 agonist) and nicotine on sensory processing as assessed by auditory deviance detection and indexed by the mismatch negativity (MMN) event-related potential. It was hypothesized that nabilone would impair auditory discriminability as shown by diminished MMN amplitudes, but not when administered in combination with nicotine. 20 male non-smokers and non-cannabis-users were assessed using a 5-stimulus 'optimal' multi-feature MMN paradigm within a randomized, placebo controlled design (placebo; nabilone [0.5â¯mg]; nicotine [6â¯mg]; and nicotineâ¯+â¯nabilone). Treatment effects were region- and deviant-dependent. At the temporal regions (mastoid sites), MMN was reduced by nabilone and nicotine separately, whereas co-administration resulted in no impairment. At the frontal region, MMN was enhanced by co-administration of nicotine and nabilone, with no MMN effects being found with separate treatment. These neural effects have relevance for sensory/cognitive processes influenced by separate and simultaneous use of cannabis and tobacco and may have treatment implications for disorders associated with sensory dysfunction and impairments in endocannabinoid and nicotinic cholinergic neurotransmission.
Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/análogos & derivados , Potenciais Evocados Auditivos/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Estimulação Acústica/métodos , Adulto , Agonistas de Receptores de Canabinoides/administração & dosagem , Método Duplo-Cego , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Quimioterapia Combinada/métodos , Eletroencefalografia/métodos , Eletroculografia/métodos , Lobo Frontal/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Masculino , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptores Nicotínicos/metabolismo , Esquizofrenia/tratamento farmacológico , Lobo Temporal/efeitos dos fármacos , Adulto JovemRESUMO
Several new antiepileptic medicines became available for clinical use in the last two decades. However, the prognosis of epilepsy remains unchanged, with approximately one-third of patients continuing to have drug-resistant seizures. Because many of these patients are not candidates for curative epilepsy surgery, there is a need for new seizure medicines with better efficacy and safety profile. Recently, social media and public pressure sparked a renewed interest in cannabinoids, which had been used for epilepsy since ancient times. However, physicians have significant difficulty prescribing cannabinoids freely because of the paucity of sound scientific studies. Among the two most common cannabinoids, cannabidiol has better antiepileptic potential than tetrahydrocannabinol. The exact antiepileptic mechanism of cannabidiol is currently not known, but it modulates a number of endogenous systems and may have a novel anticonvulsant effect. However, it has broad drug-drug interactions with several agents, including inducer and inhibitor of CYP3A4 or CYP2C19. Cannabidiol can cause liver enzyme elevation, especially when co-administered with valproate. The US Food and Drug Administration (FDA) has approved pharmaceutical-grade cannabidiol oil for two childhood-onset catastrophic epilepsies: Dravet syndrome and Lennox-Gastaut syndrome. The Drug Enforcement Agency also reclassified this product as a schedule V agent. However, other cannabidiol products remain as a schedule I substance and are primarily used without regulation. Additionally, the FDA-approved pharmaceutical-grade cannabidiol oil is expensive, and insurance companies might approve this only for the designated indications. In despair, many individuals may resort to unregulated medical cannabis products in an attempt to control seizures. Rather than spontaneous treatment without medical supervision, adequate medical oversight is indicated to monitor and manage the proper dose, side effects, validity of the product, and drug-drug interactions.
Assuntos
Canabidiol/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Epilepsias Mioclônicas/tratamento farmacológico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Resultado do Tratamento , Canabidiol/administração & dosagem , Canabidiol/efeitos adversos , Agonistas de Receptores de Canabinoides/administração & dosagem , Agonistas de Receptores de Canabinoides/efeitos adversos , HumanosRESUMO
Diabetes mellitus is a complex, multifactorial disorder that is attributed to pancreatic ß cell dysfunction. Pancreatic ß cell dysfunction results in declining utilization of glucose by peripheral tissues as kidney and it leads to nephropathy. Excessive production and accumulation of free radicals and incapable antioxidant defense system lead to impaired redox status. Macromolecular damage may occur due to impaired redox status and also immune imbalance. Δ9-Tetrahydrocannabinol (THC) is the main active ingredient in cannabis. THC acts as an immunomodulator and an antioxidant agent. Our aim was to evaluate the effects of THC in the diabetic kidney. We analyzed macromolecular damage biomarkers as protein carbonyl (PCO), lipid hydroperoxide (LHP), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and antioxidant defense system biomarkers as thiol fractions (T-SH, NP-SH, P-SH) and Cu/Zn-superoxide dismutase activity for the antioxidative effects of THC. Furthermore, mRNA expression of Krüppel-like factor-4, secreted immunopositive cell number changes of interleukin-6, nuclear factor κß (NF-κß), and peroxisome proliferator-activated receptor-γ and tumor necrosis factor α (TNF-α) levels were analyzed for the immunomodulatory activity of THC. Diabetic rats showed significantly increased levels of PCO, LHP, MDA, and 8-OHdG when compared with controls (P < 0.05 for each parameter). THC significantly reduced the elevated levels of PCO and 8-OHdG (P < 0.05 for both parameters) and also LHP and MDA levels were insignificantly reduced by THC. Also, thiol fractions insignificantly increased in THC administered diabetic kidney when compared with diabetic rats. The NF-κß cell number significantly decreased in the diabetic rats treated with THC compared with the diabetic group. According to our data, THC has ameliorative effects on the impaired redox status of diabetic kidney and also it acts as an immunomodulator. Therefore, THC might be used as a therapeutic agent for diabetic kidneys but its usage in the healthy kidney may show adverse effects.
Assuntos
Agonistas de Receptores de Canabinoides/administração & dosagem , Citocinas/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Dronabinol/administração & dosagem , Fatores de Transcrição Kruppel-Like/genética , Animais , Biomarcadores/metabolismo , Agonistas de Receptores de Canabinoides/farmacologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Dronabinol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase , Fator 4 Semelhante a Kruppel , Masculino , Oxirredução/efeitos dos fármacos , Ratos , EstreptozocinaRESUMO
BACKGROUND AND PURPOSE: It has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate adverse effects of Δ9 -tetrahydrocannabinol (THC). We determined whether CBD ameliorates cognitive deficits and withdrawal signs induced by cannabinoid CB1 /CB2 receptor agonists or produces these pharmacological effects on its own. EXPERIMENTAL APPROACH: The effects of THC or the CB1 /CB2 receptor full agonist WIN55212 alone, CBD alone or their combination were tested across a range of doses. Cognitive effects were assessed in C57BL/6 mice in a conditional discrimination task and in the Barnes maze. Cannabinoid withdrawal signs were assessed following precipitated withdrawal by acute administration of the CB1 receptor antagonist SR141716, the 5-HT1A receptor antagonist WAY100635, the TRPV1 receptor antagonist capsazepine or the adenosine A2A receptor antagonist SCH58261. KEY RESULTS: THC produced significant motor and cognitive impairment in the Barnes maze task, none of which were attenuated by the addition of CBD. CBD alone did not affect cognitive performance. Precipitation of withdrawal signs by SR141716 occurred in mice chronically treated with THC or WIN55,212. These withdrawal signs were not attenuated by addition of chronic CBD. Chronic treatment with CBD alone did not induce withdrawal signs precipitated by SR141716 or WAY100635. Chronic CBD treatment also produced anxiolysis, which was not altered by attempting to precipitate withdrawal-induced anxiety with a range of antagonists. CONCLUSIONS AND IMPLICATIONS: CBD as a monotherapy may prove to be a safer pharmacological agent, than CB1 receptor agonists alone or in combination with CBD, for the treatment of several disorders. LINKED ARTICLES: This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.
Assuntos
Canabidiol/farmacologia , Agonistas de Receptores de Canabinoides/efeitos adversos , Cannabis/química , Cognição/efeitos dos fármacos , Dronabinol/efeitos adversos , Síndrome de Abstinência a Substâncias/prevenção & controle , Animais , Canabidiol/administração & dosagem , Canabidiol/isolamento & purificação , Agonistas de Receptores de Canabinoides/administração & dosagem , Agonistas de Receptores de Canabinoides/síntese química , Antagonistas de Receptores de Canabinoides/farmacologia , Dronabinol/administração & dosagem , Dronabinol/síntese química , Camundongos , Camundongos Endogâmicos C57BL , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/agonistas , Síndrome de Abstinência a Substâncias/etiologia , Síndrome de Abstinência a Substâncias/metabolismoRESUMO
No medications are approved for cannabis use disorder (CUD). Gamma-aminobutyric acid (GABA) reuptake is modulated by cannabinoid (CB) receptor agonists, and there are shared effects between CB agonists and the GABA reuptake inhibitor tiagabine. This overlapping neuropharmacology suggested that tiagabine might be useful for CUD. The study determined the ability of tiagabine maintenance to reduce cannabis self-administration using a placebo-controlled, double-blind, counterbalanced, within-subjects design. Nontreatment-seeking daily cannabis users (N = 12; 3 female, 9 male) completed two 12-day outpatient maintenance phases (0 or 12 mg of tiagabine/day). Each phase consisted of a safety session, 7 maintenance days, and 4 experimental sessions. During experimental sessions, maintenance continued and participants completed two 2-day blocks of sampling and self-administration sessions to determine the reinforcing effects of smoked cannabis (0% and 5.9% Δ9-tetrahydrocannabinol). Naturalistic cannabis use, the subjective, performance and physiological response to cannabis, as well as side effects, sleep quality, craving, other self-reported substance use, and observer ratings were also measured. Cannabis functioned as a reinforcer and produced prototypical effects (e.g., increased heart rate and ratings of "high"), but tiagabine generally did not impact the effects of cannabis, or alter naturalistic use. Furthermore, tiagabine produced small, but significant, increases on 2 subscales of a Marijuana Craving Questionnaire, and reductions in both the amount of time slept in the past 24 hr and ratings of positive mood upon awakening. These human laboratory results from a sample of nontreatment-seeking cannabis users do not support the potential efficacy of 12 mg of tiagabine as a stand-alone pharmacotherapy for CUD. (PsycINFO Database Record
Assuntos
Fissura/efeitos dos fármacos , Abuso de Maconha/tratamento farmacológico , Abuso de Maconha/psicologia , Fumar Maconha/tratamento farmacológico , Fumar Maconha/psicologia , Tiagabina/administração & dosagem , Adulto , Afeto/efeitos dos fármacos , Afeto/fisiologia , Agonistas de Receptores de Canabinoides/administração & dosagem , Agonistas de Receptores de Canabinoides/farmacologia , Cannabis/efeitos adversos , Fissura/fisiologia , Método Duplo-Cego , Dronabinol/administração & dosagem , Feminino , Inibidores da Captação de GABA/administração & dosagem , Alucinógenos/administração & dosagem , Humanos , Masculino , Abuso de Maconha/diagnóstico , Uso da Maconha/psicologia , Reforço Psicológico , Autoadministração , Sono/efeitos dos fármacos , Sono/fisiologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: There is a clear need for advancing the treatment of cannabis use disorders. Prior research has demonstrated that dronabinol (oral THC) can dose-dependently suppress cannabis withdrawal and reduce the acute effects of smoked cannabis. The present study was conducted to evaluate whether high-dose dronabinol could reduce cannabis self-administration among daily users. METHODS: Non-treatment seeking daily cannabis users (Nâ¯=â¯13) completed a residential within-subjects crossover study and were administered placebo, low-dose dronabinol (120â¯mg/day; 40â¯mg tid), or high-dose dronabinol (180-240â¯mg/day; 60-80â¯mg tid) for 12 consecutive days (order counterbalanced). During each 12-day dronabinol maintenance phase, participants were allowed to self-administer smoked cannabis containing <1% THC (placebo) or 5.7% THC (active) under forced-choice (drug vs. money) or progressive ratio conditions. RESULTS: Participants self-administered significantly more active cannabis compared with placebo in all conditions. When active cannabis was available, self-administration was significantly reduced during periods of dronabinol maintenance compared with placebo maintenance. There was no difference in self-administration between the low- and high-dose dronabinol conditions. CONCLUSIONS: Chronic dronabinol dosing can reduce cannabis self-administration in daily cannabis users and suppress withdrawal symptoms. Cannabinoid agonist medications should continue to be explored for therapeutic utility in the treatment of cannabis use disorders.