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At least 235 records · Page 13Linked to original sources
PubMed1995

45Ca accumulation in rat brain after closed head injury; attenuation by the novel neuroprotective agent HU-211.

45Ca accumulation was studied autoradiographically as a marker for lethally injured brain tissue following closed head injury (CHI), and applied to an investigation of the neuroprotective effect of the non-psychoactive cannabinoid (+)-(3S,4S)-7-hydroxy-D-6 tetrahydro-cannabinol 1,1-dimethylheptyl (HU-211). Amassment of 45Ca in rat brain was examined 24 or 72 h after induction of CHI in the left hemisphere by a weight-drop device. Concentration of 45Ca within 15 different brain regions was assessed by relative optical density. There was increased 45Ca accumulation in the hemisphere ipsilateral to the side of the insult as compared with the contralateral hemisphere. The highest density of radioactive labeling was found in the anterior cortex and in the frontal parts of the parietal cortex, with accumulation expanding as a function of time post injury. On the third day following trauma the amount of accumulated 45Ca was higher than that at 24 h after CHI, with more distant 45Ca-accumulating structures involved: the ventral posterolateral nucleus of the thalamus and the substantia nigra. Histological examination revealed necrotic tissue in the regions accumulating 45Ca. HU-211, a stereoselective inhibitor of the N-methyl-D-aspartate (NMDA) receptor, was injected immediately after induction of trauma. One day after trauma, HU-211 had significantly decreased both the volume of the 45Ca accumulating zone and the concentration of the amassed radioisotope. In the HU-211 treated rats a considerable reduction in radioactive labeling was also found 72 h after trauma. The ability of HU-211 to decrease 45Ca accumulation after head trauma is probably due to its ability to attenuate Ca2+ fluxes through the NMDA receptor-mediated calcium channels and to reduce the depolarization evoked Ca2+ fluxes. On the basis of our results, HU-211 seems to be a promising therapeutic agent for head trauma in humans.

Animals↗
PubMed1976

Antitussive activity of some naturally occurring cannabinoids in anesthetized cats.

Experimental cough was elicited in pentobarbital-anesthetized cats by either electrical stimulation of the superior laryngeal nerve or by mechanical stimulation of the tracheal mucosa. Intravenous administration of delta9-tetrahydrocannabinol (THC) effectively reduced the amplitude of the cough response in both these models of experimentally induced cough with ED50 values (AtD50) of 1.84 and 0.78 mg/kg, respectively. This cough suppressant activity of THC was more similar to codeine-PO4 than dextromethorphan-HBr. On the other hand, both cannabinol (CBN) and cannabidiol (CBD) were devoid of antitussive activity at doses as high as 10.0 mg/kg.

Animals↗
PubMed1983

Possible role of prostaglandins in the effects of the cannabinoids on adenylate cyclase activity.

In vitro, the cannabinoids delta 9-tetrahydrocannabinol (delta 9-THC), 11-OH-delta 9-THC, cannabidiol and cannabinol all increased adenylate cyclase activity in mouse cerebral cortical homogenates. Levonantradol, a synthetic cannabinoid analog, also increased adenylate cyclase activity while its optical isomer dextronantradol did not. The increases in enzyme activity produced by the active compounds were biphasic with significant increases at 10 microM and/or 30 microM concentrations with return to control levels at 100 microM. The increases did not occur in the absence of added GTP nor did delta 9-THC have any effect on fluoride-stimulation of adenylate cyclase activity. The prostaglandin synthetase inhibitors acetyl salicylic acid and indomethacin and the phospholipase A2 inhibitor quinacrine all abolished the increase in adenylate cyclase activity produced by delta 9-THC, suggesting the involvement of prostaglandins in this cannabinoid action.

Adenosine Triphosphate↗
PubMed1987

Activation of phospholipase A2 by cannabinoids. Lack of correlation with CNS effects.

Cannabinoids delta 1-tetrahydrocannabinol, cannabinol, cannabidiol and cannabigerol have been shown to affect directly the activity of phospholipase A2 in a cell-free assay. The compounds produced a biphasic activation of the enzyme, with EC50 values in the range 6.0-20.0 X 10(-6) M and IC50 values in the range 50.0-150.0 X 10(-6) M. These results correlated well with the relative potencies reported for the stimulation of prostaglandin release from human synovial cells in vitro, confirming that activation of phospholipase A2 is the predominant action of cannabinoids on arachidonate metabolism in tissue culture. However, since delta 1-tetrahydrocannabinol is unique among these compounds in possessing cataleptic activity, it is unlikely that phospholipase A2 is the major receptor mediating the psychotropic effects of cannabis.

Animals↗
PubMed1990

Pharmacological evaluation of water soluble cannabinoids and related analogs.

The two water-soluble cannabinoids 1-[(4-morpholino) butyryloxy]-delta 8-tetrahydro-cannabinol (MB-delta 8-THC) and 5'-trimethylammonium (TMA)-delta 8-THC, as well as structurally similar compounds, were evaluated for cannabimimetic activity in the mouse (locomotor activity, tail-flick antinociception, rectal temperature, and ring-immobility) and dog (static-ataxia) procedures. MB-delta 8-THC possesses full cannabimimetic activity and is approximately equipotent to delta 8-THC. 5'-TMA-delta 8-THC only possesses partial cannabimimetic activity in that it is inactive in the ring-immobility and static-ataxia procedures. However, this analog is potent in other respects. All alterations at the 5' position do not necessarily produce this spectrum of effects, as evidenced by the pharmacological activity of 5'-bromo-delta 8-THC, 5'-OH-delta 8-THC acetate, and 5'-N-dimethyl-delta 8-THC.

Analysis of Variance↗
PubMed1991

Tetrahydrocannabinol treatment suppresses growth restriction of Legionella pneumophila in murine macrophage cultures.

Legionella pneumophila is a facultative intracellular pathogen which readily grows in human and guinea pig macrophages and in peritoneal exudate macrophages from A/J mice. Macrophage cultures capable of supporting the growth of Legionella can be used to test the potency of biologically active substances suspected of modulating host mechanisms of resistance to infection. Accordingly, this model was used to evaluate the influence of delta-9-tetrahydro-cannabinol (THC) on macrophage resistance to infection with an intracellular pathogen. Pretreatment of the macrophages with THC in the concentration range of 2.5 micrograms/ml (8 microM) to 5.0 micrograms/ml (16 microM) had little if any effect on the ability of the macrophages to either ingest or support the replication of Legionella. However, THC treatment of cells following Legionella infection resulted in increased numbers of bacteria recoverable from the macrophage cultures. Stimulation of the macrophage cultures with the activating agent lipopolysaccharide (LPS) was effective in reducing the ability of Legionella to grow in the cells. However, treatment of the LPS activated macrophages with THC resulted in greater growth of the Legionella in the cultures, indicating that the drug abolished the LPS induced enhanced resistance. These results demonstrate that THC treatment of macrophages following infection rather than before infection with Legionella promotes the replication of the bacteria within the macrophages. In addition, drug treatment suppresses the growth restricting potential of macrophages activated by LPS.

Animals↗
PubMed1987

Cannabinoid inhibition of adenylate cyclase: relative activity of constituents and metabolites of marihuana.

delta 9Tetrahydrocannabinol (THC) has been shown to inhibit the activity of adenylate cyclase in the N18TG2 clone of murine neuroblastoma cells. The concentration of delta 9THC exhibiting half-maximal inhibition was 500 nM. delta 8Tetrahydrocannabinol was less active, and cannabinol was only partially active. Cannabidiol, cannabigerol, cannabichromene, olivetol and compounds having a reduced length of the C3 alkyl side chain were inactive. The metabolites of delta 8THC and delta 9THC hydroxylated at the C11 position were more potent than the parent drugs. However, hydroxylation at the C8 position of the terpenoid ring resulted in loss of activity. Compounds hydroxylated along the C3 alkyl side chain were equally efficacious but less potent than delta 9THC. These findings are compared to the pharmacology of cannabinoids reported for psychological effects in humans and behavioral effects in a variety of animal models.

Adenylyl Cyclase Inhibitors↗
PubMed1995

Discriminative stimulus effects of CP 55,940 and structurally dissimilar cannabinoids in rats.

CP 55,940 is a potent synthetic bicyclic cannabinoid analog that has been used in a number of studies as a radioligand for the cannabinoid receptor. This compound shares behavioral and biochemical properties with naturally occurring cannabinoids such as delta 9-THC. The purpose of the present study was 3-fold: to establish the ability of CP 55,940 to serve as a discriminative stimulus, to determine whether this discriminative stimulus is identical to that of delta 9-THC, and to examine whether a newly developed cannabinoid antagonist, SR141716A, would antagonize the discriminative stimulus effects of CP 55,940. Rats were trained to discriminate 0.1 mg/kg CP 55,940 from vehicle in standard 2-lever operant conditioning chambers. CP 55,940 produced dose-dependent generalization from the training dose in dose-effect determinations conducted before and after testing with other drugs. The effects of the training dose of CP 55,940 were dose-dependently antagonized by co-administration of SR141716A. Results of substitution tests showed that delta 9-THC, WIN 55,212-2, and cannabinol substituted completely for CP 55,940 in a dose-dependent manner; however, CP 55,940 was approx 10-fold more potent than any of the other drugs in producing CP 55,940-like discriminative stimulus effects. Several drugs with CNS depressant properties (phencyclidine, haloperidol and diazepam) failed to produce reliable substitution for CP 55,940. These results demonstrate that CP 55,940 has discriminative stimulus effects and that it shares these effects with structurally dissimilar compounds that, like CP 55,940, bind to the cannabinoid receptor. Further, these effects are blocked by SR141716A, a cannabinoid receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMedDate not supplied

Delta 9-tetrahydrocannabinol produced discrimination in pigeons.

In an operant situation pigeons learned to peck one response key 90 min after an injection of 0.25mg/kg delta9-tetrahydrocannabinol (delta9-THC) and another key when trained nondrugged. When tested with doses of delta9-THC lwer than the training dose the birds disciminated 0.20 mg/kg of the drug from the nondrugged state but not 0.15 mg/kg or lower doses. The animals were able to discriminate the drug state from the nondrugged 180 min but not 360 min after the injection At a shorter interval (45 min) both drug and nondrug responding appeared. Cannabinol and cannabidiol (4.0 - 8.0 mg/kg) did not elicit any drug responses, nor did pentobarbital, ditran or amphetamine. Tests with LSD resulted in both drug and nondrug responding. When administering noncannabinoid drugs in combination with delta9-THC 0.15 mg/kg the birds responded at the key associated with the drug state, suggesting interactional effects.

Animals↗
PubMedDate not supplied

Delta-9-tetrahydrocannabinol, EEG and behavior:the importance of adaptation to the testing milieu.

Delta-9-Tetrahydrocannabinol (delta-9-THC) in doses of 0.01, 0.05, 0.1, 0.5, and 1.0 mg/kg, i.v. was administered to adult rabbits previously adapted to the testing chamber. Additionally, a group of rabbits not adapted to any part of the testing regimen was administered 1.0 mg/kg delta-9-THC. Cortical and hippocampal electroencephalographs as well as postural and activity behaviors of the unrestrained animals were recorded. In the adapted rabbits, there were dose-related increased in cortical voltage output, disruption of hippocampal theta rhythm and cortical polyspike bursts. Behaviorally, there was a dose-related tendency for standing and exploration to decrease, and at 0.5 and 1.0 mg/lh, delta-9-THC produced sprawling. In the nonadapted rabbits, administration of 1.0 mg/kh of the drug caused EEG and behavioral stimulation followed by depression of both, The results suggest that the bahavioral actions of cannabinols are largely dependent upon the animal's existing state of arousal.

Adaptation, Physiological↗
PubMed1976

Comparative effects of various naturally occurring cannabinoids on food, sucrose and water consumption by rats.

The effects of intraperitoneally injected detla9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD) were compared to d-amphetamine sulfate (d-AMP) on food and water consumption and intake of two different concentrations of sucrose solutions. Three groups of rats were given the following dietary regimens within a 6-hr feed period day: 1 - water and dry food; 2 - water, dry food and five percent sucrose solution; 3 - water, dry food and 20% sucrose solution. Food and water consumption were dramatically reduced by each test drug at feeding periods immediately following and in some instances up to 4 days after dosing in all 3 groups. However, sucrose consumption was much less affected by each cannabinoid, inidcating a preference for sweet calories, whereas d-AMP had an equal anorexic action on both food and sucrose consumption. These data suggest for the first time in rats that a preference for sweet calories occurs during an overall anorexic effect of THC, CBN and CBD.

Animals↗
PubMed1980

Post-swim grooming in mice inhibited by dopamine receptor antagonists and by cannabinoids.

After a period of swimming, mice engaged in vigorous grooming activity. This behaviour was inhibited in a dose dependent manner by dopamine receptor antagonists and by the cannabinoids, delta 9-tetrahydrocannabinol and cannabinol. Cannabidiol was inactive. It is suggested that the post-swin grooming behaviour involves a dopaminergic mechanism. The mechanism of action of the cannabinoids on this behaviour is unknown.

Animals↗
PubMed1991

Comparative in vitro metabolism of the cannabinoids.

The metabolism of delta-9-tetrahydrocannabinol (delta-9-THC), delta-8-THC, delta-11-THC, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG) and the equatorial-isomer of hexahydrocannabinol (HHC) was studied in microsomal preparations obtained from rats, mice, guinea pigs, rabbits, hamsters, gerbils and a cat. Identification of metabolites was by GC/MS and quantification by gas chromatography. Major metabolites were monohydroxylated compounds but the pattern of hydroxylation varied considerably between the species, no doubt reflecting the variable nature of the cytochrome P-450 mixed-function oxidases. Although the primary carbon allylic to the endocyclic double bond of tricyclic cannabinoids was usually the major site of attack, the 4' (side-chain, omega-1 position) and the terpene ring were usually favoured by the cat and hamster respectively. The guinea pig generally produced more metabolites hydroxylated in the side-chain (all positions) than did the other species. The results from HHC were very similar to those from THC, namely hydroxylation at C-11 in most species, and the production of high concentrations of 8 alpha-hydroxy-HHC in the mouse and 8 beta-hydroxy-HHC in the hamster. As this molecule lacks the double bond of the THCs and, hence, the allylic nature of C-11 and C-8, the results suggest that it is the orientation of the molecule to the active site of the cytochrome P-450 mixed-function oxidase rather than the reactivity of the C-H bond that governs the position of hydroxylation.

Animals↗
PubMed1991

Cannabinoids inhibit fertilization in sea urchins by reducing the fertilizing capacity of sperm.

Delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) inhibit fertilization in the sea urchin Strongylocentrotus purpuratus by reducing the fertilizing capacity of the sperm. Sperm fertility depends upon their motility, and their capacity to undergo the acrosome reaction upon encountering a specific ligand derived from the egg's jelly coat. The acrosome reaction involves exocytosis of the acrosomal granule at the apex of the sperm head and elongation of the acrosomal filament. This process exposes the sperm membrane that will attach to and fuse with the egg. Pretreatment of sperm with THC prevents the triggering of the acrosome reaction by solubilized egg jelly in a dose and time dependent manner. Motility of THC-treated sperm is not reduced compared to control sperm in sea water or vehicle dissolved in sea water. The adverse effects of THC on the acrosome reaction and sperm-fertilizing capacity are reversible. Studies with ionophores suggest that THC blocks the acrosome reaction by affecting event(s) in the stimulation-secretion coupling mechanism in the sperm preceding the opening of ion channels. Ultrastructural studies show that THC, CBD and CBN block the membrane fusion reaction between the sperm's plasma membrane and the acrosomal membrane that normally is elicited in response to stimulation by egg jelly to initiate the acrosome reaction. However, lipid deposits are found in the subacrosomal and centriolar fossae of cannabinoid treated sperm. The nuclear envelope is fragmented in close proximity to the lipid deposits within the subacrosomal fossa. These morphological observations suggest that cannabinoids may activate phospholipase(s) within the sperm. Biochemical studies show that THC activates phospholipase A2 activity in sperm homogenates.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrosome↗
PubMed1991

Influence of marihuana on cellular structures and biochemical activities.

Cannabinoids are known to affect a number of cellular systems and functions, but the basis for their action is unclear. In this paper we review the current evidence describing cannabinoid effects on various levels of cellular structure and activity and we present our current studies on the influence of delta-9-tetrahydrocannabinol, cannabidiol and cannabinol on one cellular system, the cytoskeleton. The organization of two cytoskeletal structures, microtubules and microfilaments, were examined and the mRNA levels of tubulin and actin, the major protein components of microtubules and microfilaments, respectively, were analysed.

Animals↗
PubMed1994

In vitro activation of brain protein kinase C by the cannabinoids.

The cannabinoids have been shown to affect both membrane lipid ordering and the activities of several membrane-associated proteins. We have investigated the effects of the cannabinoids on protein kinase C, a lipid-dependent enzyme that functions as an important regulator of signal-transduction processes in the brain. The naturally occurring cannabinoid delta 9-tetrahydrocannabinol (delta 9-THC) increased the activity of protein kinase C isolated from rat forebrain at concentrations of 10 microM and above. 11-OH-delta 9-THC, cannabinol and cannabidiol also increased protein kinase C activity in the same concentration range. delta 9-THC (10 microM) decreased the Kact of protein kinase C for calcium from 28 microM to 18 microM and had no effect on the phosphatidylserine concentration-stimulation relationship. At a concentration of 30 microM, delta 9-THC increased the binding of [3H]phorbol-12,13-dibutyrate ([3H]PDBu) to protein kinase C and decreased the Kd for [3H]PDBu from 8.2 nM to 5.4 nM. delta 9-THC also had effects on lipid ordering of PS micelles, producing a significant increase in the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene at a concentration of 10 microM. These data suggest that delta 9-THC activates protein kinase C via a novel mechanism, possibly as a result of effects on vesicle lipid physical characteristics.

Animals↗
PubMedDate not supplied

Selective inhibition of the binding of 3H-(3-MeHis2) thyrotropin releasing hormone to rat amygdala membranes by some naturally occurring cannabinoids.

The effect of naturally occurring cannabinoids, delta 9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD), on the brain receptors for thyrotropin releasing hormone (TRH) was investigated. TRH receptors were labeled with 3H-(3-MeHis2)TRH (3H-MeTRH). 3H-MeTRH bound specifically to rat brain membranes at a single high affinity site with a Bmax value of 49.2 +/- 0.96 fmol per mg protein and a Kd value of 3.83 +/- 0.12 nM. The binding of 3H-MeTRH to whole brain membranes was inhibited when rats were injected intraperitoneally with 3 to 30 mg/kg of THC. The extent of inhibition in the binding at 10 and 30 mg/kg was similar. THC (10 mg/kg) significantly inhibited the binding of 3H-MeTRH to amygdala membranes but did not affect the binding to membranes prepared from hippocampus, septum, cortex, striatum and the rest of the brain. THC, CBN and CBD in doses of 3 to 30 mg/kg did not affect the binding of 3H-MeTRH to hypothalamic membranes. All the three cannabinoids at 30 mg/kg inhibited the binding of 3H-MeTRH to amygdala membranes. The inhibition in the binding of 3H-MeTRH by the cannabinoids was due to changes in the Kd values but the Bmax values remained unchanged. It is concluded that both psychotomimetic and nonpsychotomimetic cannabinoids inhibit the binding of 3H-MeTR to amygdala membranes selectively, which is accomplished by decreases in the affinity of the ligand to receptors, and the amygdala may be an important brain area in some of the actions of cannabinoids.

Amygdala↗
PubMed1991

Suppression of neuropathic pain behavior in rats by a non-psychotropic synthetic cannabinoid with NMDA receptor-blocking properties.

HU211 is a novel synthetic derivative of tetrahydro-cannabinol (THC), the active marijuana ingredient. The stereochemistry of HU211 is enantiomeric to that of THC. In contrast to THC, HU211 is not psychotropic. This agent exhibits other types of biological activities; it is a non-competitive NMDA receptor blocker and has antinociceptive activity when injected with cupric chloride. This study examined its effects in autotomy, a behavioral model of neuropathic pain. Autotomy, a behavior of self-mutilation of denervated areas, was induced in Sabra rats by cutting the sciatic and saphenous nerves. We found that injections of HU211 (2.5 mg/kg) with cupric chloride (0.8 mg/kg) every 2nd day markedly suppressed autotomy during the injection period by delaying its average onset day and reducing the incidence of severe autotomy. Moreover, suppression of autotomy was retained in the postinjection period (for at least 30 days) but only when the drug was injected intraperitoneally. Lesser effects were achieved by subcutaneous injections. Cupric chloride or HU211 alone were ineffective. The general behavior and open field motor activity indicated that the effects of HU211 with Cu++ on autotomy were not due to sedation or ataxia but presumably due to antinociception mediated by NMDA receptor blockade.

Animals↗