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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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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.
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.
Jane E Lauckner - One of the best experts on this subject based on the ideXlab platform.
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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.
Daniela Parolaro - One of the best experts on this subject based on the ideXlab platform.
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changes in rat spleen Cannabinoid receptors after chronic cp 55 940 an autoradiographic study
Pharmacology Biochemistry and Behavior, 1997Co-Authors: Paola Massi, Gabriela Patrini, Tiziana Rubino, Domenica Fuzio, Daniela ParolaroAbstract:Abstract We examined whether Cannabinoid receptor density changes in the rat spleen after in vivo chronic exposure to Cannabinoids. Rats received daily injections of 0.4 mg/kg IP of the synthetic Cannabinoid receptor ligand CP-55,940 for 11 days. One h after the last injection on day 11, the rats were killed and spleen coronal sections were processed for receptor binding autoradiography with 10 nM of [ 3 H]CP-55,940 in the absence or presence of unlabeled CP-55,940 (10 μM). Densitometric analysis of the autoradiograms showed significant loss of [ 3 H]CP-55,940 binding of about 42% in chronic Cannabinoid-treated, tolerant rats. Our findings indicate that Cannabinoid receptors basically present in immune spleen cells are down-regulated by chronic exposure to Cannabinoids, suggesting a role in immune modulation and in the impairment of immune function.
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.
