The Experts below are selected from a list of 17460 Experts worldwide ranked by ideXlab platform
Ken Mackie - One of the best experts on this subject based on the ideXlab platform.
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broad and region specific impacts of the synthetic cannabinoid cp 55 940 in adolescent and adult female mouse brains
Frontiers in Molecular Neuroscience, 2018Co-Authors: Emma Leishman, Ken Mackie, Michelle N Murphy, Michelle I Murphy, Heather B BradshawAbstract:Relative to Δ9-tetrahydrocannabinol (THC), the synthetic cannabinoid CP 55,940 (CP) is significantly more potent and efficacious at cannabinoid receptors, the primary targets for endogenous Cannabinoids (eCBs). eCBs belong to a large, interconnected lipidome of bioactive signaling molecules with a myriad of effects in optimal and pathological function. Recreational use of highly potent and efficacious synthetic Cannabinoids is common amongst adolescents, potentially impacting brain development. Knowledge of the molecular outcomes of synthetic cannabinoid use will be important to develop more targeted therapies for synthetic cannabinoid intoxication and to prevent long-term disruption to the CNS. Here, we test the hypothesis that CP has age and region-dependent effects on the brain lipidome. Adolescent (post-natal day (PND) 35 and PND 50) and young adult female mice were given either an acute dose of CP or vehicle and brains were collected 2 hours later. 8 brain regions were dissected and levels of ~80 lipids were screened from each region using HPLC/MS/MS. CP had widespread effects on the brain lipidome in all age groups. Interestingly, more changes were observed in the PND 35 mice and more were reductions in a lipid’s concentration, including region-dependent lowering of eCB levels. CP levels were highest in the cortex at PND 35, the hippocampus at PND 50, and in the cerebellum in the adult. These data provide novel insights into how high-potency, synthetic Cannabinoids drive different, age-dependent, cellular signaling effects in the brain.
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cannabinoid receptors where they are and what they do
Journal of Neuroendocrinology, 2008Co-Authors: Ken MackieAbstract:The endocannabinoid system consists of the endogenous Cannabinoids (endoCannabinoids), cannabinoid receptors and the enzymes that synthesise and degrade endoCannabinoids. Many of the effects of Cannabinoids and endoCannabinoids are mediated by two G protein-coupled receptors (GPCRs), CB(1) and CB(2), although additional receptors may be involved. CB(1) receptors are present in very high levels in several brain regions and in lower amounts in a more widespread fashion. These receptors mediate many of the psychoactive effects of Cannabinoids. CB(2) receptors have a more restricted distribution, being found in a number of immune cells and in a few neurones. Both CB(1) and CB(2) couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. Thus, partial agonism, functional selectivity and inverse agonism all play important roles in determining the cellular response to specific cannabinoid receptor ligands.
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gpr55 is a cannabinoid receptor that increases intracellular calcium and inhibits m current
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Jane E Lauckner, Huei Ying Chen, Huichen Lu, Jill B Jensen, Bertil Hille, Ken MackieAbstract:The CB1 cannabinoid receptor mediates many of the psychoactive effects of Δ9THC, the principal active component of cannabis. However, ample evidence suggests that additional non-CB1/CB2 receptors may contribute to the behavioral, vascular, and immunological actions of Δ9THC and endogenous Cannabinoids. Here, we provide further evidence that GPR55, a G protein-coupled receptor, is a cannabinoid receptor. GPR55 is highly expressed in large dorsal root ganglion neurons and, upon activation by various Cannabinoids (Δ9THC, the anandamide analog methanandamide, and JWH015) increases intracellular calcium in these neurons. Examination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calcium increase to involve Gq, G12, RhoA, actin, phospholipase C, and calcium release from IP3R-gated stores. GPR55 activation also inhibits M current. These results establish GPR55 as a cannabinoid receptor with signaling distinct from CB1 and CB2.
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gpr55 is a cannabinoid receptor that increases intracellular calcium and inhibits m current
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Jane E Lauckner, Huei Ying Chen, Huichen Lu, Jill B Jensen, Bertil Hille, Ken MackieAbstract:The CB1 cannabinoid receptor mediates many of the psychoactive effects of Δ9THC, the principal active component of cannabis. However, ample evidence suggests that additional non-CB1/CB2 receptors may contribute to the behavioral, vascular, and immunological actions of Δ9THC and endogenous Cannabinoids. Here, we provide further evidence that GPR55, a G protein-coupled receptor, is a cannabinoid receptor. GPR55 is highly expressed in large dorsal root ganglion neurons and, upon activation by various Cannabinoids (Δ9THC, the anandamide analog methanandamide, and JWH015) increases intracellular calcium in these neurons. Examination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calcium increase to involve Gq, G12, RhoA, actin, phospholipase C, and calcium release from IP3R-gated stores. GPR55 activation also inhibits M current. These results establish GPR55 as a cannabinoid receptor with signaling distinct from CB1 and CB2.
Manuel Guzman - One of the best experts on this subject based on the ideXlab platform.
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Cannabinoids induce glioma stem like cell differentiation and inhibit gliomagenesis
Journal of Biological Chemistry, 2007Co-Authors: Tania Aguado, Arkaitz Carracedo, Manuel Guzman, Guillermo Velasco, Raphael Mechoulam, Boris Julien, Garry Milman, Luis Alvarez, Ismael GalveroperhAbstract:Glioma stem-like cells constitute one of the potential origins of gliomas, and therefore, their elimination is an essential factor for the development of efficient therapeutic strategies. Cannabinoids are known to exert an antitumoral action on gliomas that relies on at least two mechanisms: induction of apoptosis of transformed cells and inhibition of tumor angiogenesis. However, whether Cannabinoids target human glioma stem cells and their potential impact in gliomagenesis are unknown. Here, we show that glioma stem-like cells derived from glioblastoma multiforme biopsies and the glioma cell lines U87MG and U373MG express cannabinoid type 1 (CB1) and type 2 (CB2) receptors and other elements of the endocannabinoid system. In gene array experiments, CB receptor activation altered the expression of genes involved in the regulation of stem cell proliferation and differentiation. The cannabinoid agonists HU-210 and JWH-133 promoted glial differentiation in a CB receptor-dependent manner as shown by the increased number of S-100β- and glial fibrillary acidic protein-expressing cells. In parallel, Cannabinoids decreased the cell population expressing the neuroepithelial progenitor marker nestin. Moreover, cannabinoid challenge decreased the efficiency of glioma stem-like cells to initiate glioma formation in vivo, a finding that correlated with decreased neurosphere formation and cell proliferation in secondary xenografts. Gliomas derived from cannabinoid-treated cancer stem-like cells were characterized with a panel of neural markers and evidenced a more differentiated phenotype and a concomitant decrease in nestin expression. Overall, our results demonstrate that Cannabinoids target glioma stem-like cells, promote their differentiation, and inhibit gliomagenesis, thus giving further support to their potential use in the management of malignant gliomas.
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a pilot clinical study of δ9 tetrahydrocannabinol in patients with recurrent glioblastoma multiforme
British Journal of Cancer, 2006Co-Authors: Manuel Guzman, Guillermo Velasco, Cristina Blazquez, Ismael Galveroperh, M J Duarte, J Ravina, M Rosa, Cristina Sanchez, Luis GonzalezferiaAbstract:Δ9-Tetrahydrocannabinol (THC) and other Cannabinoids inhibit tumour growth and angiogenesis in animal models, so their potential application as antitumoral drugs has been suggested. However, the antitumoral effect of Cannabinoids has never been tested in humans. Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration. We also evaluated THC action on the length of survival and various tumour-cell parameters. A dose escalation regimen for THC administration was assessed. Cannabinoid delivery was safe and could be achieved without overt psychoactive effects. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% confidence interval: 15–33). Δ9-Tetrahydrocannabinol inhibited tumour-cell proliferation in vitro and decreased tumour-cell Ki67 immunostaining when administered to two patients. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of Cannabinoids.
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Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress related genes
Cancer Research, 2006Co-Authors: Arkaitz Carracedo, Meritxell Gironella, Mar Lorente, Stephane Garcia, Manuel Guzman, Guillermo Velasco, Juan L IovannaAbstract:Pancreatic adenocarcinomas are among the most malignant forms of cancer and, therefore, it is of especial interest to set new strategies aimed at improving the prognostic of this deadly disease. The present study was undertaken to investigate the action of Cannabinoids, a new family of potential antitumoral agents, in pancreatic cancer. We show that cannabinoid receptors are expressed in human pancreatic tumor cell lines and tumor biopsies at much higher levels than in normal pancreatic tissue. Studies conducted with MiaPaCa2 and Panc1 cell lines showed that cannabinoid administration (a) induced apoptosis, (b) increased ceramide levels, and (c) up-regulated mRNA levels of the stress protein p8. These effects were prevented by blockade of the CB(2) cannabinoid receptor or by pharmacologic inhibition of ceramide synthesis de novo. Knockdown experiments using selective small interfering RNAs showed the involvement of p8 via its downstream endoplasmic reticulum stress-related targets activating transcription factor 4 (ATF-4) and TRB3 in Delta(9)-tetrahydrocannabinol-induced apoptosis. Cannabinoids also reduced the growth of tumor cells in two animal models of pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading of pancreatic tumor cells. Moreover, cannabinoid administration selectively increased apoptosis and TRB3 expression in pancreatic tumor cells but not in normal tissue. In conclusion, results presented here show that Cannabinoids lead to apoptosis of pancreatic tumor cells via a CB(2) receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress-related genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer.
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prevention of alzheimer s disease pathology by Cannabinoids neuroprotection mediated by blockade of microglial activation
The Journal of Neuroscience, 2005Co-Authors: Belen G Ramirez, Manuel Guzman, Cristina Blazquez, Teresa Gomez Del Pulgar, Maria L De CeballosAbstract:Alzheimer's disease (AD) is characterized by enhanced beta-amyloid peptide (betaA) deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of Cannabinoids after betaA treatment, both in vivo and in vitro. Here, we show that senile plaques in AD patients express cannabinoid receptors CB1 and CB2, together with markers of microglial activation, and that CB1-positive neurons, present in high numbers in control cases, are greatly reduced in areas of microglial activation. In pharmacological experiments, we found that G-protein coupling and CB1 receptor protein expression are markedly decreased in AD brains. Additionally, in AD brains, protein nitration is increased, and, more specifically, CB1 and CB2 proteins show enhanced nitration. Intracerebroventricular administration of the synthetic cannabinoid WIN55,212-2 to rats prevent betaA-induced microglial activation, cognitive impairment, and loss of neuronal markers. Cannabinoids (HU-210, WIN55,212-2, and JWH-133) block betaA-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-alpha release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB2-selective agonist. Moreover, Cannabinoids abrogate microglia-mediated neurotoxicity after betaA addition to rat cortical cocultures. Our results indicate that cannabinoid receptors are important in the pathology of AD and that Cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.
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prevention of alzheimer s disease pathology by Cannabinoids neuroprotection mediated by blockade of microglial activation
The Journal of Neuroscience, 2005Co-Authors: Belen G Ramirez, Manuel Guzman, Cristina Blazquez, Teresa Gomez Del Pulgar, Maria L De CeballosAbstract:Alzheimer9s disease (AD) is characterized by enhanced β-amyloid peptide (βA) deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo . This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of Cannabinoids after βA treatment, both in vivo and in vitro . Here, we show that senile plaques in AD patients express cannabinoid receptors CB 1 and CB 2 , together with markers of microglial activation, and that CB 1 -positive neurons, present in high numbers in control cases, are greatly reduced in areas of microglial activation. In pharmacological experiments, we found that G-protein coupling and CB 1 receptor protein expression are markedly decreased in AD brains. Additionally, in AD brains, protein nitration is increased, and, more specifically, CB 1 and CB 2 proteins show enhanced nitration. Intracerebroventricular administration of the synthetic cannabinoid WIN55,212-2 to rats prevent βA-induced microglial activation, cognitive impairment, and loss of neuronal markers. Cannabinoids (HU-210, WIN55,212-2, and JWH-133) block βA-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-α release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB 2 -selective agonist. Moreover, Cannabinoids abrogate microglia-mediated neurotoxicity after βA addition to rat cortical cocultures. Our results indicate that cannabinoid receptors are important in the pathology of AD and that Cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.
Zvi Vogel - One of the best experts on this subject based on the ideXlab platform.
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differential transcriptional profiles mediated by exposure to the Cannabinoids cannabidiol and δ9 tetrahydrocannabinol in bv 2 microglial cells
British Journal of Pharmacology, 2012Co-Authors: Ana Juknat, Maciej Pietr, Ewa Kozela, Neta Rimmerman, Rivka Levy, Giovanni Coppola, Daniel H Geschwind, Zvi VogelAbstract:BACKGROUND AND PURPOSE Apart from their effects on mood and reward, Cannabinoids exert beneficial actions such as neuroprotection and attenuation of inflammation. The immunosuppressive activity of Cannabinoids has been well established. However, the underlying mechanisms are largely unknown. We previously showed that the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD) differ in their anti-inflammatory signalling pathways.
Mark Connor - One of the best experts on this subject based on the ideXlab platform.
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brodifacoum does not modulate human cannabinoid receptor mediated hyperpolarization of att20 cells or inhibition of adenylyl cyclase in hek 293 cells
PeerJ, 2019Co-Authors: Shivani Sachdev, Rochelle Boyd, Natasha L Grimsey, Marina Santiago, Mark ConnorAbstract:Background Synthetic Cannabinoids are a commonly used class of recreational drugs that can have significant adverse effects. There have been sporadic reports of co-consumption of illicit drugs with rodenticides such as warfarin and brodifacoum (BFC) over the past 20 years but recently, hundreds of people have been reported to have been poisoned with a mixture of synthetic Cannabinoids and BFC. We have sought to establish whether BFC directly affects cannabinoid receptors, or their activation by the synthetic cannabinoid CP55940 or the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). Methods The effects of BFC on the hyperpolarization of wild type AtT20 cells, or AtT20 cells stably expressing human CB1- or CB2- receptors, were studied using a fluorescent assay of membrane potential. The effect of BFC on CB1- and CB2-mediated inhibition of forskolin-stimulated adenylyl cyclase (AC) activation was measured using a BRET assay of cAMP levels in HEK 293 cells stably expressing human CB1 or CB2. Results BFC did not activate CB1 or CB2 receptors, or affect the hyperpolarization of wild type AtT20 cells produced by somatostatin. BFC (1 µM) did not affect the hyperpolarization of AtT20-CB1 or AtT20-CB2 cells produced by CP55940 or Δ9-THC. BFC (1 µM) did not affect the inhibition of forskolin-stimulated AC activity by CP55940 in HEK 293 cells expressing CB1 or CB2. BFC (1 µM) also failed to affect the desensitization of CB1 and CB2 signaling produced by prolonged (30 min) application of CP55940 or Δ9-THC to AtT20 cells. Discussion BFC is not a cannabinoid receptor agonist, and appeared not to affect cannabinoid receptor activation. Our data suggests there is no pharmacodynamic rationale for mixing BFC with synthetic Cannabinoids; however, it does not speak to whether BFC may affect synthetic cannabinoid metabolism or biodistribution. The reasons underlying the mixing of BFC with synthetic Cannabinoids are unknown, and it remains to be established whether the "contamination" was deliberate or accidental. However, the consequences for people who ingested the mixture were often serious, and sometimes fatal, but this seems unlikely to be due to BFC action at cannabinoid receptors.
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brodifacoum does not modulate human cannabinoid receptor mediated hyperpolarization of att20 cells or inhibition of adenylyl cyclase in hek 293 cells
bioRxiv, 2019Co-Authors: Shivani Sachdev, Rochelle Boyd, Natasha L Grimsey, Mark ConnorAbstract:BackgroundSynthetic Cannabinoids are a commonly used class of recreational drugs that can have significant adverse effects. There have been sporadic reports of co-consumption of illicit drugs with rodenticides such as warfarin and brodifacoum (BFC) over the past 20 years but recently, hundreds of people have been reported to have been poisoned with a mixture of synthetic Cannabinoids and BFC. We have sought to establish whether BFC directly affects cannabinoid receptors, or their activation by the synthetic cannabinoid CP55940 or the phytocannabinoid {Delta}9-tetrahydrocannabinol ({Delta}9-THC).nnMethodsThe effects of BFC on the hyperpolarization of wild type AtT20 cells, or AtT20 cells stably expressing human CB1- and CB2-mediated receptors, were studied using a fluorescent assay of membrane potential. The effects of BFC on CB1 and CB2 mediated inhibition of forskolin-stimulated adenylyl cyclase (AC) activation was measured using a BRET assay of cAMP levels in HEK 293 cells stably expressing human CB1 and CB2.nnResultsBFC did not activate CB1 or CB2 receptors, or affect the hyperpolarization of wild type AtT20 cells produced by somatostatin. BFC (10 {micro}M) did not affect the hyperpolarization of AtT20-CB1 or AtT20-CB2 cells produced by CP55940 or {Delta}9-THC. BFC (1 {micro}M) did not affect the inhibition of forskolin-stimulated AC activity by CP55940 in HEK 293 cells expressing CB1 or CB2. BFC (1 {micro}M) also failed to affect the desensitization of CB1 and CB2 signalling produced by prolonged (30 min) application of CP55940 or {Delta}9-THC to AtT20 cells.nnDiscussionBFC is not a cannabinoid receptor agonist, and appeared not to affect cannabinoid receptor activation. Our data suggests there is no pharmacodynamic rationale for mixing BFC with synthetic Cannabinoids, however, it does not speak to whether BFC may affect synthetic cannabinoid metabolism or biodistribution. The reasons underlying the mixing of BFC with synthetic Cannabinoids are unknown, and it remains to be established whether the "contamination" was deliberate or accidental. However, the consequences for people who ingested the mixture were often serious, and sometimes fatal, but this seems unlikely to be due to BFC action at cannabinoid receptors.
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actions of Cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro
Molecular Pharmacology, 2000Co-Authors: Christopher W Vaughan, Mark Connor, Elena E Bagley, Macdonald J ChristieAbstract:The midbrain periaqueductal gray (PAG) is a major site of cannabinoid-mediated analgesia in the central nervous system. In the present study, we examined the actions of Cannabinoids on rat PAG neurons in vitro. In brain slices, superfusion of the cannabinoid receptor agonist WIN55,212-2 inhibited electrically evoked inhibitory and excitatory postsynaptic currents in all PAG neurons. The endogenous cannabinoid anandamide inhibited evoked inhibitory postsynaptic currents in the presence of the anandamide transport inhibitor AM404, but not in its absence. The stable anandamide analog R1-methanandamide also inhibited evoked inhibitory postsynaptic currents. WIN55,212-2 reduced the rate of spontaneous miniature inhibitory postsynaptic currents in normal and Ca(2+)-free solutions, but had no effect on their amplitude distributions or kinetics. The WIN55,212-2-induced decrease in miniature inhibitory postsynaptic current rate was concentration dependent (EC(50) = 520 nM). The effects of Cannabinoids were reversed by the CB(1) receptor antagonist SR141716. WIN55,212-2 produced no change in membrane current or conductance in PAG neurons in brain slices and had no effect on Ca(2+)-channel currents in acutely isolated PAG neurons. These findings suggest that Cannabinoids act via CB(1) receptors to inhibit GABAergic and glutamatergic synaptic transmission in rat PAG, although the efficacy of endogenous Cannabinoids is likely to be limited by uptake and breakdown. Like mu-opioids, Cannabinoids act to reduce the probability of transmitter release from presynaptic terminals via a Ca(2+)-independent mechanism. In contrast to mu-opioids, Cannabinoids have no direct postsynaptic actions on PAG neurons. Thus, Cannabinoids and mu-opioids are likely to produce analgesia within PAG in part by different mechanisms.
Andreas Zimmer - One of the best experts on this subject based on the ideXlab platform.
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immunomodulation by Cannabinoids is absent in mice deficient for the cannabinoid cb2 receptor
European Journal of Pharmacology, 2000Co-Authors: Nancy E Buckley, Tom I Bonner, Kathleen L Mccoy, Eva Mezey, Anne M Zimmer, Christian C Felder, Michelle Glass, Andreas ZimmerAbstract:Abstract Cannabinoids have immunomodulatory as well as psychoactive effects. Because the central cannabinoid receptor (cannabinoid CB 1 receptor) is highly expressed in many neuronal tissues and the peripheral cannabinoid receptor (cannabinoid CB 2 receptor) is highly expressed in immune cells, it has been suggested that the central nervous system effects of Cannabinoids are mediated by cannabinoid CB 1 receptors and that the immune effects are mediated by cannabinoid CB 2 receptors. To test this hypothesis, we have generated the first mouse strain with a targeted mutation in the cannabinoid CB 2 receptor gene. Binding studies using the highly specific synthetic cannabinoid receptor agonist (−)- cis -3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]- trans -4-(3-hydroxypropyl)cyclohexanol ([ 3 H]CP 55,940) revealed no residual cannabinoid binding sites in the spleen of the cannabinoid CB 2 receptor knockout mice, while binding in the central nervous system was unchanged. Cannabinoid CB 2 receptor knockout mice, which appear healthy, are fertile and care for their offspring. Fluorescence activated cell sorting (FACS) analysis showed no differences in immune cell populations between cannabinoid CB 2 receptor knockout and wildtype mice. We investigated the immunomodulatory effects of Cannabinoids in cannabinoid CB 2 receptor deficient mice using a T cell co-stimulation assay. Δ 9 Tetrahydrocannabinol inhibits helper T cell activation through macrophages derived from wild type, but not from knockout mice, thus indicating that this effect is mediated by the cannabinoid CB 2 receptor. In contrast, central nervous system effects of Cannabinoids were not altered in these mice. Our results suggest that cannabinoid CB 2 receptor-specific ligands may be clinically useful in the modulation of macrophage immune function while exhibiting no central nervous system activity. Furthermore, we conclude that the cannabinoid CB 2 receptor knockout mouse is a useful animal model in which to study the role of the cannabinoid system in immunoregulation.
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immunomodulation by Cannabinoids is absent in mice deficient for the cannabinoid cb2 receptor
European Journal of Pharmacology, 2000Co-Authors: Nancy E Buckley, Tom I Bonner, Kathleen L Mccoy, Eva Mezey, Anne M Zimmer, Christian C Felder, Michelle Glass, Andreas ZimmerAbstract:Cannabinoids have immunomodulatory as well as psychoactive effects. Because the central cannabinoid receptor (cannabinoid CB(1) receptor) is highly expressed in many neuronal tissues and the peripheral cannabinoid receptor (cannabinoid CB(2) receptor) is highly expressed in immune cells, it has been suggested that the central nervous system effects of Cannabinoids are mediated by cannabinoid CB(1) receptors and that the immune effects are mediated by cannabinoid CB(2) receptors. To test this hypothesis, we have generated the first mouse strain with a targeted mutation in the cannabinoid CB(2) receptor gene. Binding studies using the highly specific synthetic cannabinoid receptor agonist (-)-cis-3-?2-Hydroxy-4-(1, 1-dimethylheptyl)phenyl-trans-4-(3-hydroxypropyl)cyclohexanol (?3HCP 55,940) revealed no residual cannabinoid binding sites in the spleen of the cannabinoid CB(2) receptor knockout mice, while binding in the central nervous system was unchanged. Cannabinoid CB(2) receptor knockout mice, which appear healthy, are fertile and care for their offspring. Fluorescence activated cell sorting (FACS) analysis showed no differences in immune cell populations between cannabinoid CB(2) receptor knockout and wildtype mice. We investigated the immunomodulatory effects of Cannabinoids in cannabinoid CB(2) receptor deficient mice using a T cell co-stimulation assay. Delta(9)Tetrahydrocannabinol inhibits helper T cell activation through macrophages derived from wild type, but not from knockout mice, thus indicating that this effect is mediated by the cannabinoid CB(2) receptor. In contrast, central nervous system effects of Cannabinoids were not altered in these mice. Our results suggest that cannabinoid CB(2) receptor-specific ligands may be clinically useful in the modulation of macrophage immune function while exhibiting no central nervous system activity. Furthermore, we conclude that the cannabinoid CB(2) receptor knockout mouse is a useful animal model in which to study the role of the cannabinoid system in immunoregulation.
