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排序方式: 共有552条查询结果,搜索用时 31 毫秒
41.
Cannabinoids are usually defined ambiguously in either botanical, chemical or pharmacological frames of reference. For researchers attempting to dissect out useful agents with some, but not all of the pharmacological effects of marijuana, this is not a trivial, semantic issue, since designation of a compound as a cannabinoid carries with it an overlay of public perception and administrative policy concerns. A pharmacological definition is advocated, based primarily on the ability of compounds to be subjectively generalized from Δ9-THC. The alternate term cannabimimetic is advocated to signify such activity. Thus, compounds lacking the subjective effects of Δ9-THC, regardless of structural similarity, would not then be impeded by the often-deleterious cannabinoid label, while compounds sharing the subjective effect of Δ9-THC would be appropriately classified, despite structural divergence from the prototype. 相似文献
42.
Developing cannabinoid-based medication along with marijuana's recreational use makes it important to investigate molecular adaptations the endocannabinoid system undergoes following prolonged use and withdrawal. Repeated cannabinoid administration results in development of tolerance and produces withdrawal symptoms that may include seizures. Here we employed electrophysiological and immunochemical techniques to investigate the effects of prolonged CB1 receptor agonist exposure on cultured hippocampal neurons. Approximately 60% of CB1 receptors colocalize to GABAergic terminals in hippocampal cultures. Prolonged treatment with the cannabinamimetic WIN 55,212-2 (+ WIN, 1 μM, 24 h) caused profound CB1 receptor downregulation accompanied by neuronal hyperexcitability. Furthermore, prolonged + WIN treatment resulted in increased GABA release as indicated by increased mIPSC frequency, a diminished GABAergic inhibition as indicated by reduction in mIPSC amplitude and a reduction in GABAA channel number. Additionally, surface staining for the GABAA β2/3 receptor subunits was decreased, while no changes in staining for the presynaptic vesicular GABA transporter were observed, indicating that GABAergic terminals remained intact. These findings demonstrate that agonist-induced downregulation of the CB1 receptor in hippocampal cultures results in neuronal hyperexcitability that may be attributed, in part, to alterations in both presynaptic GABA release mechanisms and postsynaptic GABAA receptor function demonstrating a novel role for cannabinoid-dependent presynaptic control of neuronal transmission. 相似文献
43.
Charles A. Lunn Jay Fine Alberto Rojas-Triana James V. Jackson Brian Lavey Joseph A. Kozlowski R. William Hipkin Daniel J. Lundell Loretta Bober 《Immunopharmacology and immunotoxicology》2007,29(3):387-401
Work to improve the therapeutic properties of cannabinoid CB2 receptor-selective inverse agonists has led to the development of Sch.036, an aryl substituted triaryl bis-sulfone with improved oral pharmacokinetic parameters. In this report, we show that this compound blocks in vivo trafficking of various leukocyte populations, a property consistent with other members of this chemical series. This CB2-selective compound also shows efficacy in leukocyte recruitment models when added in concert with suboptimal doses of selected anti-inflammatory agents, consistent with its unique function and indicative of its potential therapeutic utility. Finally, studies with Sch.036 show that this cannabinoid CB2-specific inverse agonist can ameliorate bone damage in a rat model of relapsing-remitting arthritis. This result suggests that a cannabinoid CB2-selective inverse agonist may help ameliorate a particularly harmful property of this inflammatory joint disease. 相似文献
44.
Julián Romero J.Javier Fernández-Ruiz Gema Vela Mariano Ruiz-Gayo J.Angel Fuentes J.Antonio Ramos 《Drug and alcohol dependence》1998,50(3):393-249
The present study was designed to test the possible existence of changes in brain cannabinoid receptors in morphine-dependent mice. To this end, we compared cannabinoid receptor binding and WIN 55,212-2-stimulated [35S]guanylyl-5′-O-(γ-thio)-triphosphate ([35S]GTPγS) binding in several brain regions of mice chronically exposed to morphine or saline. The existence of opiate dependence in morphine-injected mice was assessed by analyzing the well-known jumping behavior induced by the blockade of opioid receptors with naloxone, whereas these animals were unresponsive to the blockade of cannabinoid receptors with SR141716. The different structures analyzed exhibited similar cannabinoid receptor binding levels in morphine-dependent and control mice, with the only exception of the globus pallidus, which exhibited a very small, but statistically significant, increase. In addition, the activation of cannabinoid receptors with WIN 55,212-2 increased [35S]GTPγS binding in most of the structures examined. The increase was of similar magnitude in morphine-dependent and control mice, except in the substantia nigra, where morphine-dependent mice exhibited lesser [35S]GTPγS binding levels in basal conditions, although a significantly higher WIN 55,212-2-stimulated binding. Other structures, such as the central gray substance, where there was a poor agonist-induced stimulation in control mice, exhibited, however, higher levels of WIN 55,212-2-stimulated [35S]GTPγS binding in morphine-dependent mice, whereas these animals tended to exhibit a higher [35S]GTPγS binding levels in basal conditions, although a lesser and not statistically significant WIN 55,212-2-stimulated binding, in the deep layers of the cerebral cortex. Thus, the data support the potential existence of a specific effect of morphine in the coupling of cannabinoid receptors to GTP-binding proteins, rather than on receptor binding, although this was observed only in the substantia nigra and central gray substance. 相似文献
45.
Evidence for a role of endogenous cannabinoids in the modulation of acute and tonic pain sensitivity
Nicole M Strangman Saundra L Patrick Andrea G Hohmann Kang Tsou J.Michael Walker 《Brain research》1998,813(2):653
The competitive CB1 receptor antagonist SR141716A was used to test the hypothesis that endogenous cannabinoids modulate tonic pain sensitivity. Pretreatment with the antagonist significantly enhanced the response to a chemical nociceptive stimulus in the formalin test. Postreatment with the antagonist 5 min following the induction of tonic pain produced hyperalgesia during the tonic phase only. These findings suggest that endogenous cannabinoids serve naturally to modulate the maintenance of pain following repeated noxious stimulation. 相似文献
46.
Barbara Malinowska Grzegorz Godlewski Bernard Bucher E. Schlicker 《Naunyn-Schmiedeberg's archives of pharmacology》1997,356(2):197-202
The effects of two cannabinoid receptor agonists, R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]-pyrrolo[1, 2, 3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone
(WIN 55,212-2) and (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP-55,940), were studied on (i) the vasopressor response elicited in pithed rats by electrical stimulation of the sympathetic
outflow and (ii) the release of 3H-noradrenaline and the vasoconstriction elicited in isolated rat tail arteries by transmural electrical stimulation. In pithed
rats, the electrical (1Hz for 10s) stimulation of the preganglionic sympathetic nerve fibres increased diastolic blood pressure
by about 30mmHg. This neurogenic vasopressor response (which under the conditions of our study was almost exclusively due
to the release of catecholamines) was decreased by WIN 55-212,2 and CP-55,940 in a dose-dependent manner (inhibition by WIN
55,212-2 and CP-55,940, 0.1μmol/kg each, about 25–30%). The inhibition was identical in adrenalectomized rats and in animals
with intact adrenals. The inhibitory action of WIN 55,212-2 and CP-55,940 was abolished by a dose of 0.03μmol/kg of the CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlo- rophenyl)-4-methyl-3-pyrazole-carboxamide (SR 141716), which, by itself, had no effect. WIN 55,212-2, CP-55,940 and SR 141716 failed to affect the vasopressor response to exogenous
noradrenaline (1nmol/kg), which also increased diastolic blood pressure by about 30mmHg. In isolated rat tail arteries, the
electrically (0.4Hz) evoked tritium overflow and vasoconstriction were not modified by WIN 55,212-2 and CP-55,940 (1μmol/l
each). In conclusion, the neurogenic vasopressor response in the pithed rat can be modulated via cannabinoid CB1 receptors probably located presynaptically on the postganglionic sympathetic nerve fibres innervating resistance vessels.
Received: 4 April 1997 / Accepted: 10 May 1997 相似文献
47.
E. Schlicker J. Timm J. Zentner M. Göthert 《Naunyn-Schmiedeberg's archives of pharmacology》1997,356(5):583-589
We examined the question of whether cannabinoid receptors modulating noradrenaline release are detectable in the brain of
humans and experimental animals. For this purpose, hippocampal slices from humans, guinea-pigs, rats and mice and cerebellar,
cerebrocortical and hypothalamic slices from guinea-pigs were incubated with [3H]noradrenaline and then superfused. Tritium overflow was evoked either electrically (0.3 or 1Hz) or by introduction of Ca2+ ions (1.3μM) into Ca2+-free, K+-rich medium (25μM) containing tetrodotoxin 1μM. Furthermore, the cAMP accumulation stimulated by forskolin 10μM was determined
in guinea-pig hippocampal membranes. We used the following drugs: the cannabinoid receptor agonists (–)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol
(CP-55,940) and R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone (WIN 55,212-2), the inactive S(–)-enantiomer of the latter (WIN 55,212-3) and the CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR 141716). The electrically evoked tritium overflow from guinea-pig hippocampal slices was reduced by WIN 55,212-2 (pIC30% 6.5) but not affected by WIN 55,212-3 up to 10μM. The concentration-response curve of WIN 55,212-2 was shifted to the right
by SR 141716 (0.032μM) (apparent pA2 8.2), which by itself did not affect the evoked overflow. WIN 55,212-2 1μM also inhibited the Ca2+-evoked tritium overflow in guinea-pig hippocampal slices and the electrically evoked overflow in guinea-pig cerebellar, cerebrocortical
and hypothalamic slices as well as in human hippocampal slices but not in rat and mouse hippocampal slices. SR 141716 (0.32μM)
markedly attenuated the WIN 55,212-2-induced inhibition in guinea-pig and human brain slices. SR 141716 0.32μM by itself increased
the electrically evoked tritium overflow in guinea-pig hippocampal slices but failed to do so in slices from the other brain
regions of the guinea-pig and in human hippocampal slices. The cAMP accumulation stimulated by forskolin was reduced by CP-55,940
and WIN 55,212-2. The concentration-response curve of CP 55,940 was shifted to the right by SR 141716 (0.1μM; apparent pA2 8.3), which by itself did not affect cAMP accumulation. In conclusion, cannabinoid receptors of the CB1 subtype occur in the human hippocampus, where they may contribute to the psychotropic effects of cannabis, and in the guinea-pig
hippocampus, cerebellum, cerebral cortex and hypothalamus. The CB1 receptor in the guinea-pig hippocampus is located presynaptically, is activated by endogenous cannabinoids and may be negatively
coupled to adenylyl cyclase.
Received: 5 June 1997 / Accepted: 6 August 1997 相似文献
48.
Seung Hwa Baek Young Ok Kim Jung Suk Kwag Kyw Eun Choi Woo Young Jung Du Seok Han 《Archives of pharmacal research》1998,21(3):353-356
Geraniol (1), olivetol (2), cannabinoids (3 and4) and 5-fluorouracil (5) were tested for their growth inhibitory effects against human oral epitheloid carcinoma cell lines (KB) and NIH 3T3 fibroblasts
using two different 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and sulforhodamine B protein
(SRB) assay. Cannabigerol (3) exhibited the highest growth-inhibitory activity against the cancer cell lines. 相似文献
49.
The objective of this study was to determine whether the development of tolerance to CP 55,940, a potent cannabinoid agonist, was due to changes in the receptor or second messenger system. ICR mice treated with CP 55,940 (2 mg/kg) twice a day for 6 and one-half days developed a high degree of tolerance to the pharmacological effects of CP 55,940. The ability of CP 55,940 to produce motor hypoactivity, hypothermia and immobility was reduced 163-, 97- and 19-fold, respectively. Evaluation of 3H-CP 55,940 binding to rat brain membranes indicated no difference in receptor affinity between the vehicle- and CP 55,940-treated animals. However, these binding studies revealed a 50% decrease in receptor number in the cerebellum of the CP 55,940-tolerant mice. Although cAMP is generally considered to be the second messenger for cannabinoid receptors, little difference was observed in the inhibitory effects of CP 55,940 on adenylyl cyclase activity in cerebellum between vehicle and drug-treated mice. However, there was an increase in receptor mRNA which suggests a compensation for receptor loss. There are several possible explanations for these results. There may be sufficient spare receptors such that CP 55,940-tolerant mice are capable of producing a maximal effect on the second messenger system. On the other hand, one could conclude that cannabinoid receptor down-regulation does not account for the development of tolerance to all of the effects of CP 55,940 in mice. 相似文献
50.
The subthalamic nucleus contains cannabinoid receptors and cannabinoid receptor mRNA. However, the role of cannabinoid receptors in this nucleus has not been examined. In order to investigate the functional role of cannabinoid receptors in the rat subthalamic nucleus, turning activity was observed following unilateral microinjection of the synthetic cannabinoid CP 55,940. CP 55,940 (10 μg) induced ipsilateral turning. This effect was blocked by coadministration of the cannabinoid receptor antagonist SR141716A (5 μg). These results suggest that cannabinoid receptors in the subthalamic nucleus mediate an inhibition of motor activity. 相似文献