Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of exogenous nucleotides on the histamine hypersensitivity of pharmacologically beta-blocked mice were investigated. Female HLA-SW (ICR) mice, 27-29 gm, were injected intraperitoneally with 20 to 100 mug of propranolol 45 min before intraperitoneal challenge with 1 mg histamine. These animals had a mortality which averaged approximately 80%. At various time intervals before histamine, doses of from 0.5 to 12 mumoles of nucleotides were administered intravenously. Noncyclic nucleotides, adenosine, adenosine 5'-monophosphate (AMP), and guanosine 5'-monophosphate (GMP) showed clear, dose-response protection against histamine death of propranolol-treated mice when they were given 45 to 90 min before histamine. Cyclic AMP showed significant protection only when it was given at a dose of 8 mumoles 45 to 90 min before histamine, and lower or higher doses gave equivocal or no protection. Cyclic GMP WAS Not protective at any dose tested. Propranolol treatment also produced enhanced sensitivity to passive systemic anaphylaxis. Mice were passively sensitized by intraperitoneal injection of mouse anti-egg albumin antibody 6 hr before intravenous challenge with 0.5 mg egg albumin. The mortality from anaphylaxis in the group treated with 20 mug propranolol 45 min before antigen challenge increased to 83%, while that of the group not given propranolol was only 10%. Nucleotides were given intravenously 45 min before antigen challenge. The nucleotides that protected mice from death due to histamine challenge also protected them from death due to systemic anaphylaxis. These protective nucleotides were the same nucleotides that had been reported previously to be protective against Bordetella pertussis-induced hypersensitivity to histamine and anaphylaxis.
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PMID:Hypersensitivity to histamine and systemic anaphylaxis in mice with pharmacologic beta adrenergic blockade: protection by nucleotides. 18 34

The release of arachidonic acid from mouse peritoneal and S49 cells induced by delta 1-tetrahydrocannabinol was found to be altered by prior exposure of the cells to either pertussis toxin or cholera toxin. The stable analogs of GTP and GDP, GTP-gamma-S and GDP-beta-S, were also effective in changing the extent of arachidonate release in saponin-treated cells. GDP-beta-S essentially abolished the THC response, while GTP-gamma-S showed effects mainly on vehicle-treated cells. The cataleptic action of THC in intact mice which is mediated by eicosanoids was also attenuated by pertussis toxin pretreatment. It is suggested that the THC receptor is coupled to phospholipases through one or more G-proteins and that adenylate cyclase probably does not have a role in this mechanism.
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PMID:G-protein mediation of cannabinoid-induced phospholipase activation. 166 19

Using a reverse transcription-coupled PCR, we demonstrated that both brain and spleen type cannabinoid receptor (CB1-R and CB2-R, respectively) mRNAs are expressed in the preimplantation mouse embryo. The CB1-R mRNA expression was coincident with the activation of the embryonic genome late in the two-cell stage, whereas the CB2-R mRNA was present from the one-cell through the blastocyst stages. The major psychoactive component of marijuana (-)-delta-9-tetrahydrocannabinol [(-)-THC] inhibited forskolin-stimulated cAMP generation in the blastocyst, and this inhibition was prevented by pertussis toxin. However, the inactive cannabinoid cannabidiol (CBD) failed to influence this response. These results suggest that cannabinoid receptors in the embryo are coupled to inhibitory guanine nucleotide binding proteins. Further, the oviduct and uterus exhibited the enzymatic capacity to synthesize the putative endogenous cannabinoid ligand arachidonylethanolamide (anandamide). Synthetic and natural cannabinoid agonists [WIN 55,212-2, CP 55,940, (-)-THC, and anandamide], but not CBD or arachidonic acid, arrested the development of two-cell embryos primarily between the four-cell and eight-cell stages in vitro in a dose-dependent manner. Anandamide also interfered with the development of eight-cell embryos to blastocysts in culture. The autoradiographic studies readily detected binding of [3H]anandamide in embryos at all stages of development. Positive signals were present in one-cell embryos and all blastomeres of two-cell through four-cell embryos. However, most of the binding sites in eight-cell embryos and morulae were present in the outer cells. In the blastocyst, these signals were primarily localized in the mural trophectoderm with low levels of signals in the polar trophectoderm, while little or no signals were noted in inner cell mass cells. These results establish that the preimplantation mouse embryo is a target for cannabinoid ligands. Consequently, many of the adverse effects of cannabinoids observed during pregnancy could be mediated via these cannabinoid receptors. Although the physiological significance of the cannabinoid ligand-receptor signaling in normal preimplantation embryo development is not yet clear, the regulation of embryonic cAMP and/or Ca2+ levels via this signaling pathway may be important for normal embryonic development and/or implantation.
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PMID:The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling. 756 54

Dose-effect curves were generated for the cannabinoids [intracerebroventricularly (icv.)] and compared with those previously generated after administration intrathecally (i.t.). The ED50 values after administration of levonantradol, CP 55,940, delta 9-THC and delta 8-THC i.t. vs. icv. did not differ significantly. CP 56,667 was significantly more potent after icv. administration than i.t. administration, and was nearly 10 times more potent than CP 55,940 (icv.). CP 55,940 and CP 56,667, which did not produce greater than additive effects in combination with morphine when the drugs were administered i.t., shifted the morphine (icv.) dose-effect curve in a parallel manner nearly 10-fold after icv. administration. The antinociceptive effects of the cannabinoids (icv.) were not blocked by ICI 174,864 (20 micrograms/mouse), nor-BNI (70 micrograms/mouse) or naloxone (20 micrograms/mouse or 10 mg/kg s.c.). Pertussis toxin pretreatment i.t. for 7 days totally abolished the antinociception produced by the cannabinoids (icv. and i.t.). Pretreatment of the mice with forskolin (i.t.) or Cl-cAMP (10 micrograms/mouse i.t.), which produced no antinociception, significantly attenuated the antinociception produced by the delta 9-THC and CP 55,940. However, when administered icv., forskolin and Cl-cAMP produced antinociception, but did not block or produce greater than additive effects with the antinociception produced by the cannabinoids administered icv. The i.t. administration of calcium and calcium modulators failed to alter the antinociception produced by the i.t. administration of the cannabinoids. Conversely, calcium (icv.) blocked the antinociceptive effects of the cannabinoids. The AD50 values (+/- CL) for calcium-induced block of delta 9-THC, delta 8-THC and CP 55,940 were 215 (94-489), 176 (122-253) and 123 (81-186) nmol/mouse, respectively. omega-Conotoxin (1 micrograms/mouse icv.), which did not alter the antinociceptive effects of delta 9-THC, significantly reversed the calcium-induced blockade of delta 9-THC. Thapsigargin (icv.) blocked the antinociception produced by delta 9-THC and CP 55,940. Apamin, blocker calcium-gated potassium channels, produced a parallel rightward shift in the dose-effect curves of delta 9-THC, delta 8-THC and CP 55,940 (i.t.). However, apamin (5 ng/mouse icv.) failed to block icv. administered cannabinoids. Because acute administration of opiates/opioids have been shown to interact with Gi/o protein-coupled receptors, decrease calcium entry to and content of neurons, reduce cAMP levels and produce hyperpolarization of neurons via both ATP- and apamin-sensitive potassium channels, these three intracellular systems may be common points of interaction with the cannabinoids.
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PMID:Modulation of cannabinoid-induced antinociception after intracerebroventricular versus intrathecal administration to mice: possible mechanisms for interaction with morphine. 781 46

The purpose of this study was to investigate whether anandamide induces cannabimimetic responses, mainly mobilization of arachidonic acid, in primary cultures of rat brain cortical astrocytes. Confluent monolayer cultures of astrocytes, prelabeled with [3H]arachidonic acid, were incubated with anandamide or delta9-tetrahydrocannabinol (delta9-THC) in the presence or absence of thimerosal, a fatty acid acyl CoA transferase inhibitor and phenylmethylsulfonyl fluoride, an amidohydrolase inhibitor. Anandamide and delta9-THC induced a time- and concentration-dependent release of arachidonic acid in the presence, but not in the absence, of thimerosal. Anandamide- and delta9-THC-stimulated arachidonic acid release was pertussis toxin-sensitive, indicating a receptor/G-protein involvement. A novel and selective cannabinoid receptor antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboximide hydrochloride], blocked the arachidonic acid release, suggesting a cannabinoid receptor-mediated pathway. In astrocytes, the magnitude of anandamide-induced arachidonic acid release was equal to that released by equimolar concentrations of delta9-THC. Furthermore, direct assay of amidohydrolase activity indicated that degradation of anandamide into arachidonic acid and ethanolamine was negligible in cortical astrocytes. Our results suggest that anandamide stimulates receptor-mediated release of arachidonic acid, and the receptor may be the cannabinoid receptor. Astrocytes, containing a cannabinoid receptor and lower or negligible amidohydrolase activity, may be an important brain cell model in which to study the cannabimimetic effects of anandamide at a cellular and molecular level.
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PMID:Anandamide- and delta9-tetrahydrocannabinol-evoked arachidonic acid mobilization and blockade by SR141716A [N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4 -methyl-1H-pyrazole-3-carboximide hydrochloride]. 861 4

Cannabinoid receptors negatively regulate adenylate cyclase through a pertussis toxin-sensitive GTP-binding protein. In the present studies, signaling via the adenylate cyclase/cAMP pathway was investigated in the murine thymoma-derived T-cell line, EL4.IL-2. Northern analysis of EL4.IL-2 cells identified the presence of 4-kilobase CB2 but not CB1 receptor-subtype mRNA transcripts. Southern analysis of genomic DNA digests for the CB2 receptor demonstrated identical banding patterns for EL4.IL-2 cells and mouse-derived DNA, both of which were dissimilar to DNA isolated from rat. Treatment of EL4.IL-2 cells with either cannabinol or Delta9-THC disrupted the adenylate cyclase signaling cascade by inhibiting forskolin-stimulated cAMP accumulation which consequently led to a decrease in protein kinase A activity and the binding of transcription factors to a CRE consensus sequence. Likewise, an inhibition of phorbol 12-myristate 13-acetate (PMA)/ionomycin-induced interleukin 2 (IL-2) protein secretion, which correlated to decreased IL-2 gene transcription, was induced by both cannabinol and Delta9-THC. Further, cannabinoid treatment also decreased PMA/ionomycin-induced nuclear factor binding to the AP-1 proximal site of the IL-2 promoter. Conversely, forskolin enhanced PMA/ionomycin-induced AP-1 binding. These findings suggest that inhibition of signal transduction via the adenylate cyclase/cAMP pathway induces T-cell dysfunction which leads to a diminution in IL-2 gene transcription.
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PMID:Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2. 866 42

Delta9-Tetrahydrocannabinol (delta9-THC) binding to cannabinoid receptors induces an inhibition in adenylate cyclase activity through the engagement of a pertussis toxin-sensitive GTP-binding protein. In this study we investigated the ramifications of decreased cyclic AMP (cAMP) formation by delta9-THC on signaling events through the cAMP pathway distal to adenylate cyclase in mouse splenocytes. Delta9-THC treatment produced a marked and concentration-related decrease in forskolin-inducible protein kinase A (PKA) activity. This decrease in kinase activity was due to an inhibition in cAMP formation and not through a direct effect on the kinase as evidenced by the fact that PKA activity could not be modulated directly by delta9-THC in the presence of exogenous cAMP. One of the primary roles of PKA in this signaling pathway is to activate transcription factors for subsequent binding to cAMP response elements (CRE) present in the promoter region of cAMP-responsive genes. In the present studies, we observed that forskolin treatment of splenocytes resulted in a rapid activation of trans-acting factor binding to the CRE, which peaked at 30-60 min and whose binding was repressed concentration dependently in the presence of delta9-THC. As with forskolin, mitogenic stimulation including anti-CD3 mAb or phorbol ester plus ionomycin treatment of splenocytes induced CRE binding activity, which was maximal around 60 min and was suppressed by delta9-THC treatment. In conclusion, these data indicate that cAMP-mediated signal transduction is inhibited by delta9-THC and consequently leads to a decrease in the activation of transcription factors that bind to CRE regulatory sites.
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PMID:Inhibition of protein kinase A and cyclic AMP response element (CRE)-specific transcription factor binding by delta9-tetrahydrocannabinol (delta9-THC): a putative mechanism of cannabinoid-induced immune modulation. 926 Aug 75

Splenocyte cultures from BALB/c mice were treated with THC and mitogen and shown to produce less Th1 cytokine, IFN gamma, and more Th2 cytokines, IL-4 and IL-10. This suggested that drug treatment caused a shift in the development of Th1 and Th2 cells. In studies designed to look at molecular mechanisms, the CBI antagonist, SR141716A, did not attenuate the THC enhancement of IL-4 production, but pertussis toxin attenuated the drug effect and the CB2 agonist, JWH-051, increased IL-4 production similar to THC. These results suggest that cannabinoids may increase Th2 development and IL-4 production in cultured immune cells through the activity of the CB2 receptor subtype. Studies are currently in progress to further define the molecular and cellular mechanisms involved.
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PMID:Cannabinoid receptors and the cytokine network. 966 74

In this study we employed the neuroblastoma x glioma NG 108-15 cell line as a model for investigating the effects of long-term activation of cannabinoid receptors on delta opioid receptor desensitization, down-regulation and gene expression. Exposure of NG 108-15 cells to (-)-delta9-tetrahydrocannabinol (delta9-THC) reduced opioid receptor binding, evaluated in intact cells, by approximately 40-45% in cells exposed for 24 h to 50 and 100 nM delta9-THC and by approximately 25% in cells exposed to 10 nM delta9-THC. Lower doses of delta9-THC (0.1 and 1 nM) or a shorter exposure time to the cannabinoid (6 h) were not effective. Down-regulation of 6 opioid receptors was not observed in cells exposed for 24 h to pertussis toxin (PTX) and then treated for 24 h with 100 nM delta9-THC. In cells that were exposed for 24 h to the cannabinoid, the ability of delta9-THC and of the delta opioid receptor agonist [D-Ser2, Leu5, Thr6]enkephalin to inhibit forskolin-stimulated cAMP accumulation was significantly attenuated. Prolonged exposure of NG 108-15 cells to 100 nM delta9-THC produced a significant elevation of steady-state levels of delta opioid receptor mRNA. This effect was not observed in cells pretreated with PTX. The selective cannabinoid receptor antagonist SR 141716A blocked the effects elicited by delta9-THC on delta opioid receptor desensitization, down-regulation and gene expression; thus indicating that these are mediated via activation of cannabinoid receptors. These data demonstrate the existence, in NG 108-15 cells, of a complex cross-talk between the cannabinoid and opioid receptors on prolonged exposure to delta9-THC triggered by changes in signaling through Gi and/or G0-coupled receptors.
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PMID:Regulation of delta opioid receptors by delta9-tetrahydrocannabinol in NG108-15 hybrid cells. 977 17

Intracerebroventricular (i.c.v.) administration to mice of delta9-tetrahydrocannabinol (delta9-THC), WIN 55,212-2 or the endogenous cannabinoid anandamide induced dose-related antinociception in the 55 degrees C warm-water tail-flick test. Pretreatment (24 h, i.c.v.) with pertussis toxin dose-dependently reduced the antinociceptive effect of delta9-THC (955 nmol), WIN 55,212-2 (30 nmol) and anandamide (135 nmol) (IC50 = 0.13, 5.5, and 0.32 nmol, respectively). In contrast, pretreatment (24 h, i.c.v.) with cholera toxin (0.1-3.0 mg) reduced the antinociception of WIN 55,212-2, had minimal effect on delta9-THC, and dose-dependently increased the antinociception of anandamide (ED50 = 0.50 nmol). These data suggest differences in the receptor-effector coupling of delta9-THC, WIN 55,212-2 and anandamide in supraspinal-induced antinociception in mice.
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PMID:Differential cholera-toxin sensitivity of supraspinal antinociception induced by the cannabinoid agonists delta9-THC, WIN 55,212-2 and anandamide in mice. 1021 3


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