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1.
Cannabis Cannabinoid Res ; 6(3): 211-220, 2021 06.
Article in English | MEDLINE | ID: mdl-34115948

ABSTRACT

Opioids are effective analgesics; however, there are many negative consequences of chronic use. One important side effect of chronic opioid use is the continuous engagement of the immune response that can exacerbate chronic pain. The opioid, morphine, initiates a Toll-like receptor 4 (TLR4) signaling cascade that drives the activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome proteins, resulting in cytokine production and effectively creating a positive feedback loop for continuous TLR4 activation. In addition to driving cytokine production, morphine drives changes in proinflammatory lipid signaling. The alteration of both cytokine and lipid signaling systems by morphine suggests that its chronic use leads to a pathological immune response that would benefit from targeted therapy. Engaging the endogenous cannabinoid system has shown therapeutic benefit, particularly regarding its anti-inflammatory and immunosuppressive effects. Promising preclinical and clinical investigations suggest that cannabidiol (CBD) is an effective adjuvant for treatment of symptoms of opioid use disorders; however, the mechanism through which CBD drives this outcome is unclear. One potential source of insight into this mechanism is in how CBD regulates immune regulators such as cytokines and lipid signaling systems, including endocannabinoids and related immune-responsive lipids. In this review, we outline the immune response to chronic opioid use as well as CBD in the context of a lipopolysaccharide-induced immune response and speculate on the mechanism of CBD as a modulator of chronic opioid-induced immune system dysregulation.


Subject(s)
Analgesics, Opioid/pharmacology , Cannabidiol/pharmacology , Morphine/pharmacology , Analgesics, Opioid/adverse effects , Analgesics, Opioid/immunology , Animals , Cannabidiol/immunology , Cytokines/pharmacology , Endocannabinoids/metabolism , Humans , Inflammasomes , Inflammation/metabolism , Lipid Metabolism , Lipopolysaccharides/pharmacology , Morphine/adverse effects , Morphine/immunology , Toll-Like Receptor 4/metabolism
2.
J Immunol ; 205(4): 987-993, 2020 08 15.
Article in English | MEDLINE | ID: mdl-32690657

ABSTRACT

Long noncoding RNAs (lncRNAs) have been demonstrated to play important regulatory roles in gene expression, from histone modification to protein stability. However, the functions of most identified lncRNAs are not known. In this study, we investigated the role of an lncRNA called AW112010. The expression of AW112010 was significantly increased in CD4+ T cells from C57BL/6J mice activated in vivo with myelin oligodendrocyte glycoprotein, Staphylococcal enterotoxin B, or in vitro with anti-CD3 anti-CD28 mAbs, thereby demonstrating that activation of T cells leads to induction of AW112010. In contrast, anti-inflammatory cannabinoids such as cannabidiol or δ-9-tetrahydrocannabinol decreased the expression of AW112010 in T cells. Interestingly, the expression of AW112010 was high in in vitro-polarized Th1 and Th17 cells but low in Th2 cells, suggesting that this lncRNA may regulate inflammation. To identify genes that might be regulated by AW112010, we used chromatin isolation by RNA purification, followed by sequencing. This approach demonstrated that AW112010 regulated the transcription of IL-10. Additionally, the level of IL-10 in activated T cells was low when the expression of AW112010 was increased. Use of small interfering RNA to knock down AW112010 expression in activated T cells led to increased IL-10 expression and a decrease in the expression of IFN-γ. Further studies showed that AW112010 interacted with histone demethylase KDM5A, which led to decreased H3K4 methylation in IL-10 gene locus. Together, these studies demonstrate that lncRNA AW112010 promotes the differentiation of inflammatory T cells by suppressing IL-10 expression through histone demethylation.


Subject(s)
Cell Differentiation/immunology , Histones/immunology , Inflammation/immunology , Interleukin-10/immunology , RNA, Long Noncoding/immunology , T-Lymphocytes/immunology , Animals , CD28 Antigens/immunology , Cannabidiol/immunology , Cell Differentiation/genetics , Chromatin/immunology , Demethylation , Dronabinol/immunology , Enterotoxins/immunology , Female , Lymphocyte Activation/immunology , Mice, Inbred C57BL , Myelin-Oligodendrocyte Glycoprotein/immunology , RNA, Messenger/immunology
3.
Brain Behav Immun ; 81: 574-587, 2019 10.
Article in English | MEDLINE | ID: mdl-31326506

ABSTRACT

Cognitive impairment is a major source of disability in schizophrenia and current antipsychotic drugs (APDs) have minimal efficacy for this symptom domain. Cannabidiol (CBD), the major non-intoxicating component of Cannabis sativa L., exhibits antipsychotic and neuroprotective properties. We recently reported the effects of CBD on cognition in male offspring of a maternal immune activation (polyinosinic-polycytidilic acid (poly I:C)) model relevant to the aetiology of schizophrenia; however, the effects of CBD treatment in females are unknown. Sex differences are observed in the onset of schizophrenia symptoms and response to APD treatment. Furthermore, the endogenous cannabinoid system, a direct target of CBD, is sexually dimorphic in humans and rodents. Therefore, the present work aimed to assess the therapeutic impact of CBD treatment on behaviour and neurochemical signalling markers in female poly I:C offspring. Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg; i.v.) or saline (control) on gestational day 15. From postnatal day 56, female offspring received CBD (10 mg/kg, i.p.) or vehicle treatment for approximately 3 weeks. Following 2 weeks of CBD treatment, offspring underwent behavioural testing, including the novel object recognition, rewarded alternation T-maze and social interaction tests to assess recognition memory, working memory and sociability, respectively. After 3 weeks of CBD treatment, the prefrontal cortex (PFC) and hippocampus (HPC) were collected to assess effects on endocannabinoid, glutamatergic and gamma-aminobutyric acid (GABA) signalling markers. CBD attenuated poly I:C-induced deficits in recognition memory, social interaction and glutamatergic N-methyl-d-aspartate receptor (NMDAR) binding in the PFC of poly I:C offspring. Working memory performance was similar between treatment groups. CBD also increased glutamate decarboxylase 67, the rate-limiting enzyme that converts glutamate to GABA, and parvalbumin protein levels in the HPC. In contrast to the CBD treatment effects observed in poly I:C offspring, CBD administration to control rats reduced social interaction, cannabinoid CB1 receptor and NMDAR binding density in the PFC, suggesting that CBD administration to healthy rats may have negative consequences on social behaviour and brain maturation in adulthood. Overall, the findings of this study support the therapeutic benefits of CBD on recognition memory and sociability in female poly I:C offspring, and provide insight into the neurochemical changes that may underlie the therapeutic benefits of CBD in the poly I:C model.


Subject(s)
Cannabidiol/immunology , Cannabidiol/pharmacology , Schizophrenia/metabolism , Animals , Antipsychotic Agents/immunology , Antipsychotic Agents/pharmacology , Behavior, Animal/physiology , Brain/metabolism , Cannabidiol/metabolism , Cognition/drug effects , Cognitive Dysfunction/immunology , Cognitive Dysfunction/metabolism , Female , Hippocampus/metabolism , Memory, Short-Term/drug effects , Neurodevelopmental Disorders/immunology , Neurodevelopmental Disorders/metabolism , Poly I-C/pharmacology , Prefrontal Cortex/metabolism , Pregnancy , Prenatal Exposure Delayed Effects/immunology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism , Recognition, Psychology/drug effects , Schizophrenia/immunology
4.
J Physiol Pharmacol ; 60 Suppl 3: 99-103, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19996489

ABSTRACT

The major non-psychoactive compound of cannabis plant, cannabidiol, has been reported to be a promising therapeutic agent for many inflammatory, autoimmune and neurodegenerative diseases. In spite of growing interest in therapeutic use of cannabidiol very little is known about its influence on the immune system. Present study aimed to evaluate lymphocyte subsets distribution in peripheral blood after repeated, systemic administration of cannabidiol. Adult male Wistar rats received intraperitoneal injections of vehicle or cannabidiol at dose of 2.5 or 5 mg/kg/day, for 14 consecutive days. Blood samples were collected one hour after the last injection. Three-color immunofluorescent antibody staining procedure (CD3-FITC/CD45RA-PC7/CD161A-APC and CD3-FITC/CD4-PC7/CD8-APC) was used for determination of T, B, NK, NKT, T helper, and T cytotoxic lymphocyte subsets. Total leukocyte number and percentage numbers of leukocyte subpopulations were also assessed. Administration of cannabidiol at dose of 5 mg/kg caused a significant decrease in total leukocyte number and a significant fall in total numbers of T, B, and both T helper and T cytotoxic lymphocyte subsets. This immunosuppressive effect did not affect the total numbers of NK and NKT cells that are responsible for the primary, nonspecific antiviral and antitumor immune response. In contrast, administration of cannabidiol at dose of 2.5 mg/kg increased the total and percentage NKT cells numbers, and the percentage number of NK cells. The results suggest that repeated treatment with cannabidiol inhibits specific immunity by reduction of T, B, T cytotoxic, and T helper cell numbers, and may enhance nonspecific antiviral and antitumor immune response related to NK and NKT cells.


Subject(s)
Cannabidiol/immunology , Immunologic Factors/immunology , Killer Cells, Natural/drug effects , Lymphocyte Subsets/drug effects , Lymphopenia/chemically induced , Natural Killer T-Cells/drug effects , Animals , Cannabidiol/pharmacology , Dose-Response Relationship, Drug , Immunologic Factors/pharmacology , Lymphocyte Subsets/cytology , Lymphopenia/immunology , Male , Rats
6.
J Lab Clin Med ; 88(2): 194-201, 1976 Aug.
Article in English | MEDLINE | ID: mdl-956682

ABSTRACT

Utilizing an indirect Coombs' technique, humoral antibodies to marihuana and its major components were found in 34 subjects with known marihuana exposure. Similar antibodies were absent in the sera of a control population of 34 subjects with no known marihuana exposure. The specificity of the antibodies was confirmed by differential absorption studies in six seropositive subjects. Routine laboratory tests were abnormal in 22 of 34 seropositive subjects and in 9 of 34 control subjects. The relationship of seropositivity to abnormal laboratory tests is not certain.


Subject(s)
Antibody Formation/drug effects , Cannabis/pharmacology , Adolescent , Adult , Antibody Specificity , Antigens , Cannabidiol/analysis , Cannabidiol/immunology , Cannabis/analysis , Cannabis/immunology , Coombs Test , Dronabinol/analogs & derivatives , Dronabinol/analysis , Dronabinol/immunology , Humans , Male
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