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PubMed2005

Mechanism of cardioprotection following trauma-hemorrhagic shock by a selective estrogen receptor-beta agonist: up-regulation of cardiac heat shock factor-1 and heat shock proteins.

Although 17beta-estradiol (E2) administration following trauma-hemorrhage (T-H) improves cardiac function in male rodents, it is not known whether the salutary effects of E2 are mediated via estrogen receptor (ER)-alpha or ER-beta, and whether cardiac heat shock proteins (Hsp) are affected by E2 administration. Male Sprague-Dawley rats underwent T-H (mean BP 40 mmHg for 90 min, then resuscitation). ER-alpha agonist propyl pyrazole triol (PPT) (5 microg/kg), ER-beta agonist diarylpropiolnitrile (DPN) (5 microg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. At 24 h after T-H or sham operation, cardiac output (CO), stroke volume (SV), mean blood pressure, and +/- dP/dt max were measured (n=6 rats per group). Cardiac Hsp32, 60, 70, and 90 mRNA/protein expressions and heat shock factor (HSF)-1 DNA binding activity were determined. One-way ANOVA and Tukey's test were used for statistical analysis. CO, SV and +/- dP/dt(max) decreased significantly after T-H, however, administration of ER-beta agonist DPN after T-H restored the above parameters. Moreover, DPN treatment prevented T-H-mediated decrease in Hsp60 mRNA/protein and Hsp90 protein expressions in the heart. Hsp32 and Hsp70 mRNA/protein expression and HSF-1 DNA binding activity in the hearts were increased even above the shams in DPN treated T-H rats. In contrast, no significant change in the above parameters was observed in T-H rats treated with ER-alpha agonist PPT. Thus, the salutary effects of E2 on cardiac function are mediated via ER-beta and ER-beta-induced up-regulation of Hsp likely plays a significant role in the E2-mediated cardioprotection after T-H.

Animals↗
PubMed1988

The increase in hepatic tyrosine aminotransferase activity by ethanol administration involves an acceleration of enzyme synthesis.

The present study was conducted to examine the nature of the increase in tyrosine aminotransferase (TAT) activity by acute ethanol administration. A significant rise in aminotransferase activity was observed as early as 1 hr after intact rats were gavaged with ethanol. Ethanol administration also increased TAT activity in adrenalectomized rats. Inhibition of ethanol metabolism by pyrazole administration had no effect on the ethanol-induced increase in TAT activity. Immunochemical analyses revealed that the enhancement of TAT activity in ethanol-fed rats correlated with an increase in aminotransferase protein. Measurement of the rate of TAT synthesis showed that in ethanol-fed rats, [3H]leucine was incorporated into the aminotransferase protein at a higher rate than in controls by a factor which was similar to the enhancement in enzyme activity. Our findings indicate that an acceleration of TAT synthesis fully accounts for the increase in TAT activity during the early stage of enzyme induction. TAT induction by ethanol administration is not dependent upon an increase in adrenal corticosteroid production, nor does it require ethanol metabolism.

Animals↗
PubMed2003

Integrity of extracellular loop 1 of the human cannabinoid receptor 1 is critical for high-affinity binding of the ligand CP 55,940 but not SR 141716A.

Like other G-protein coupled receptors with hydrophobic ligands, the human cannabinoid receptor 1 (CB1) is thought to bind its ligands within the transmembrane region of the receptor. However, for some of these receptors the extracellular loops (ECs) have also been shown to play a role in ligand recognition and selectivity. We have taken a mutagenesis approach to examine the role of the amino terminus, EC1, and EC3 of CB1 in ligand binding. Eight mutant receptors, each with a dipeptide insertion, were constructed, expressed, and evaluated for binding to the cannabinoid ligands (-)-cis-3[2-hydroxy-4-(1',1'-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP 55,940) and N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A). Mutants with insertions in the membrane distal region of the amino terminus or EC3 maintained affinity for both ligands. Those with insertions in the membrane proximal region of the amino terminus or EC1 exhibited a loss of affinity for CP 55,940 while retaining wild-type affinity for SR 141716A. Representative mutants were analyzed for agonist-induced inhibition of cyclic AMP accumulation, and the results indicated that G-protein coupling remained intact. Alanine substitution mutants were made to address whether it was the perturbation of the overall structure of the region or the displacement of particular side chains that was responsible for the loss of CP 55,940 binding. We conclude that a structurally intact EC1, but not the comparably short EC3, is essential for high-affinity CP 55,940 binding.

Amino Acid Sequence↗
PubMed1997

Interaction of brain cannabinoid receptors with guanine nucleotide binding protein: a radioligand binding study.

The binding of a classical cannabinoid agonist, [3H]R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2 ,3-de]-1,4-benzoxazin-6-yl)(1-napthalenyl)methanone monomethanesulfonate ([3H] WIN55212-2), and a selective cannabinoid receptor (CB1) antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)1-(2,4-dichlorophenyl)-4-meth yl-1H-pyrazole-3-carboxamide hydrochloride ([3H]SR141716A), to rat cannabinoid receptors was evaluated using rat cerebellar membranes. Guanine nucleotides inhibited [3H]WIN55212-2 binding by approximately 50% at 10 microM and enhanced [3H]SR141716A binding very slightly. In the same tissue, the binding of guanosine 5'-O-[gamma-[35S]thio]triphosphate ([35S]GTP-gamma-S) was characterized and the influence of cannabinomimetics evaluated on this binding. Cannabinoid receptor agonists enhanced [35S]GTP-gamma-S binding, whereas SR141716A was devoid of action by itself but antagonized the action of cannabinoid receptor agonists. The good correlation obtained between the half maximum efficient concentration (EC50) values in [35S]GTP-gamma-S binding and the IC50 values [3H]WIN55212-2 binding shows that [35S]GTP-gamma-S binding could be a good functional assay for brain cannabinoid receptors.

Animals↗
PubMed2003

The reaction of acetylacetone with amino sugars: implications for the formation of glycosylpyrazole derivatives.

Glycosylpyrazoles are efficiently formed by reaction of saccharide hydrazones with pentan-2,4-dione (acetylacetone), but in aqueous buffer, pyrazole derivatives of amino sugars couple with a further equivalent of acetylacetone affording high yields of ketoenamines. These ketoenamines were considerably more stable than the ketoenamines formed from 2-amino-2-deoxy aldoses that have been described as intermediates in the classical Elson-Morgan reaction. Moreover, high yields of perketoenamine derivatives were achieved with oligosaccharides derived from hydrolysis of chitosan. The removal of the ketoenamine moieties to regenerate the free amine was readily accomplished with aqueous hydrazine.

Amino Sugars↗
PubMed2002

The metabolic activation of abacavir by human liver cytosol and expressed human alcohol dehydrogenase isozymes.

Abacavir (ZIAGEN) is a reverse transcriptase inhibitor marketed for the treatment of HIV-1 infection. A small percentage of patients experience a hypersensitivity reaction indicating immune system involvement and bioactivation. A major route of metabolism for abacavir is oxidation of a primary betagamma unsaturated alcohol to a carboxylic acid via an aldehyde intermediate. This process was shown to be mediated in vitro by human cytosol and NAD, and subsequently the alphaalpha and gamma2gamma2 human isoforms of alcohol dehydrogenase (ADH). The alphaalpha isoform effected two sequential oxidation steps to form the acid metabolite and two isomers, qualitatively reflective of in vitro cytosolic profiles. The gamma2gamma2 isozyme generated primarily an isomer of abacavir, which was minor in the alphaalpha profiles. The aldehyde intermediate could be trapped in incubations with both isozymes as an oxime derivative. These metabolites can be rationalized as arising via the aldehyde which undergoes isomerization and further oxidation by the alphaalpha enzyme or reduction by the gamma2gamma2 isozyme. Non-extractable abacavir protein residues were generated in cytosol, and with alphaalpha and gamma2gamma2 incubations in the presence of human serum albumin (HSA). Metabolism and residue formation were blocked by the ADH inhibitor 4-methyl pyrazole (4-MP). The residues generated by the alphaalpha and gamma2gamma2 incubations were analyzed by SDS-PAGE with immunochemical detection. The binding of rabbit anti-abacavir antibody to abacavir-HSA was shown to be dependent on metabolism (i.e. NAD-dependent and 4-MP sensitive). The mechanism of covalent binding remains to be established, but significantly less abacavir-protein residue was detected with an analog of abacavir in which the double bond was removed, suggestive of a double bond migration and 1,4 addition process.

Alcohol Dehydrogenase↗
PubMed1990

Influence of some anti-inflammatory drugs on the activity of aryl hydrocarbon hydroxylase and the cytochrome P450 content.

The metabolism of benzo[a]pyrene is mediated by the mixed function oxidase system including the cytochrome P450-dependent aryl hydrocarbon hydroxylase. The data of the present study revealed the ability of various commonly used anti-inflammatory drugs to alter the activity of this enzyme system, where all the tested drugs, namely phenyl butazone, ketoprofen, piroxicam, and acetaminophen, caused an increase in both the activity of aryl hydrocarbon hydroxylase and the cytochrome P450 content whether administered as a single dose or as a repeated dose for 6 consecutive days. The percentage of change for all drugs except phenyl butazone was proportional to the duration of drug administration. On the other hand, pyrazole which is chemically related to phenyl butazone, had no significant effect when administered as a single dose but caused a decrease in both studied parameters when administered as a repeated dose for 6 consecutive days. The mechanisms by which these commonly used drugs modify the aryl hydrocarbon hydroxylase activity and the cytochrome p450 content are discussed in the text.

Acetaminophen↗
PubMed2000

Role of the endogenous cannabinoid system in the formalin test of persistent pain in the rat.

It has been suggested that administration of a cannabinoid CB(1) (SR141716A ¿N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide) and CB(2) (SR144528 ¿N-[(1S)-endo-1, 3, 3-trimethyl bicyclo ¿2.2.1 heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyr azo le- 3-carboxamide¿) receptor antagonists to mice potentiates inflammatory hyperalgesia by removing an endogenous cannabinoid tone. We examined whether the behavioural response to s.c. formalin injection in rats is similarly enhanced. A total of 30 animals received SR141716A (0.5 or 5 mg/kg) or SR144528 (0.3 or 3 mg/kg) 30 min before 1% formalin. Pain behaviour was quantified using the composite weighted pain score technique (CPS-WST(0,1,2)). An overall CPS-WST(0,1,2) was calculated for each phase and groups were compared (analysis of variance). The results obtained in the control group confirmed the characteristic biphasic behavioural response to formalin injection. None of antagonist groups had a significant increase in overall CPS-WST(0,1,2) compared to the control. Indeed, a significant decrease in CPS-WST(0,1,2) scores for both phases was detected in most of all of the groups, except SR141716A at 5 mg/kg. Levels of endogenous cannabinoids (anandamide, palmitoylethanolamide, 2-arachidonylglycerol) were measured from rats hind-paw skin 1 h after s.c. injection of 0.9% saline (100 microl), 1% (50 microl), 2. 5% (50 microl) and 5% (100 microl) formalin. The concentration of endocannabinoids did not differ between control and formalin-induced inflammation groups. The activity of anandamide amidohydrolase in hind-paw skin also did not change after treatment with formalin. In conclusion, cannabinoid antagonists do not enhance formalin-evoked pain behaviour. These results suggest that, in this model, endogenous cannabinoids do not tonically attenuate inflammatory hyperalgesia.

Animals↗
PubMed2000

Pharmacological evaluation of aerosolized cannabinoids in mice.

The reemergence on the debate of the use of marijuana for medicinal purposes has been the impetus for developing an acceptable delivery form of aerosolized cannabinoids. The goals of the present study were to: (1) develop and characterize the physical properties of an aerosolized form of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent present in marijuana; and (2) assess the pharmacological effects of cannabinoid inhalation in mice. A Small Particle Aerosol Generator (SPAG) nebulizer, used to generate the aerosol, had an output of approximately 0.154 mg/l of aerosolized Delta(9)-THC with a 2.0 microm mass median aerodynamic diameter and a 2.2 geometric standard deviation (GSD). Virtually all the particles were less than 5.0 microm in diameter suggesting that they were sufficiently small to penetrate deeply into the lungs. Inhalation exposure to aerosolized Delta(9)-THC in mice elicited antinociceptive effects that were dependent on concentration and exposure time with an estimated Delta(9)-THC dose of 1.8 mg/kg. On the other hand, inhalation exposure to Delta(9)-THC failed to produce two other indices indicative of cannabinoid activity, hypothermia and decreases in spontaneous locomotor activity. The antinociceptive effects occurred within 5 min of exposure and lasted approximately 40 min in duration. The cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), but not naloxone, blocked these antinociceptive effects (AD(50)=0.09 mg/kg) indicating a cannabinoid receptor mechanism of action. Similarly, inhalation exposure to a water soluble cannabinoid analog, 3-(5'-cyano-1', 1'dimethylheptyl)-1-(4-N-morpholinobutyrloxy)-Delta(8)-te trahydrocann abinol (O-1057), produced antinociception that was blocked by SR 141716A. These results demonstrate that the development of an aerosolized form of cannabinoids for human medicinal use is feasible.

Administration, Inhalation↗
PubMed2000

Cannabinoid CB(1) receptor agonists increase rat cortical and hippocampal acetylcholine release in vivo.

Intravenous administration of the cannabinoid CB(1) receptor agonists (R-(+)-[2, 3-Dihydro-5-methyl-3[morpholinyl)methyl]-pyrrolo[1,2,3-de]-1, 4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), WIN 55,212-2 (10, 37.5, 75 and 150 microg/kg), and ((6aR)-trans-3-(1, 1-Dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6, 6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol), HU 210 (1 and 4 microg/kg) dose-dependently increased acetylcholine release in dialysates from the prefrontal cortex and the hippocampus of freely moving rats. Administration of the cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide]HCl, SR 141716A, at a dose that per se did not affect basal acetylcholine release (2. 5 microg/kg), prevented the increase of acetylcholine release by WIN 55,212-2 (150 microg/kg i.v.) or by HU 210 (4 microg/kg i.v.) in both areas. These data demonstrate that, at low i.v. doses, the synthetic cannabinoid CB(1) receptor agonists, WIN 55,212-2 and HU 210 stimulate cortical and hippocampal acetylcholine release.

Acetylcholine↗
PubMed2000

SR 141716A enhances spatial memory as assessed in a radial-arm maze task in rats.

A tonically active endogenous cannabinoid system has been proposed to modulate learning and memory. The purpose of the present study was to determine whether administration of the cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A) would enhance memory as assessed in an eight-arm radial maze task. Because the high degree of choice accuracy in the standard radial-arm maze procedure precludes the possibility of detecting memory enhancement, the difficulty of the task was increased by imposing a delay of varying durations between a two-phase procedure consisting of acquisition and test phases. Significantly fewer errors were committed during the test phase following an injection of SR 141716A than the vehicle treatment. These results provide additional evidence supporting the hypothesis that endogenous cannabinoid systems play a role in memory processes.

Analysis of Variance↗
PubMed2000

Inhibition of small intestinal secretion by cannabinoids is CB1 receptor-mediated in rats.

We tested the hypothesis that cannabinoids, acting via a neuronal mechanism of action decrease small intestinal secretion. In vitro electrical stimulation induced ileal secretion in rats, that was attenuated by a cannabinoid receptor agonist, WIN 55212-2, (mesylate(R)-(+)-[2, 3-dihydro-5-methyl-3-[4-morpholino)methyl]pyrrolo-[1,2,3-de]-1, 4-benzoxazin-6-yl](1-naphthyl)methanone) but not its optical isomer WIN 55212-3. The inhibition of secretion induced by WIN 55212-2 was reversed by SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride), a cannabinoid CB1 receptor antagonist. An ileal secretory response stimulated by acetylcholine was unaffected by WIN 55212-2. These findings show that cannabinoids inhibit neurally mediated secretion via cannabinoid CB1 receptors. Thus, cannabinoids may have therapeutic potential for diarrhea unresponsive to available therapies.

Acetylcholine↗
PubMed2001

Inhibitory effects of SR141716A on G-protein activation in rat brain.

N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A), a cannabinoid CB(1) receptor antagonist, has inverse agonist effects in cannabinoid CB(1) receptor-expressing cell lines, brain and peripheral organs. These studies characterized SR141716A-inhibited G-protein activity by measuring [35S]GTPgammaS binding. Maximal inhibition of basal [35S]GTPgammaS binding in cerebellar membranes was 50%. The EC(50) value for inhibition of [35S]GTPgammaS binding was 4.4 microM, whereas the K(e) for inhibition of R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN 55,212-2)-stimulated [35S]GTPgammaS binding was 0.6 nM. [35S]GTPgammaS autoradiography was used to examine the regional specificity of SR141716A inhibition. SR141716A inhibited basal [35S]GTPgammaS binding in all regions examined, with inhibition ranging from approximately 20% in caudate-putamen to 40% in hippocampus. These studies demonstrate that SR141716A is a competitive antagonist at nanomolar concentrations, whereas it inhibits basal receptor-mediated G-protein activity at micromolar concentrations. These data suggest that the apparent inverse agonist effect is either not cannabinoid CB(1) receptor-specific or that SR141716A is binding to different sites on the cannabinoid CB(1) receptor to produce inverse agonist versus competitive antagonist effects.

Animals↗
PubMed2001

Critical role of the endogenous cannabinoid system in mouse pup suckling and growth.

Delta9-tetrahydrocannabinol, the active principle in marijuana, is a cannabinoid receptor agonist. Both the crude drug and delta9-tetrahydrocannabinol have been used as appetite promoters. The endogenous cannabinoid, arachidonoyl ethanolamide (anandamide), likewise a cannabinoid receptor agonist, has been shown to have the same effect. In contrast, the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide (SR141716A) reduces food intake. Here, we report that administration of SR141716A to newly born mouse pups (either a single administration on postnatal day 1, or daily for a week as of postnatal day 2) had a devastating effect on milk ingestion and growth. The first 24 h after birth appeared the most critical for the growth stunting effect of SR141716A. Death followed within 4-8 days. Co-administration of delta9-tetrahydrocannabinol almost fully reversed the effect of the antagonist in the week-long regimen. Co-administration of 2-arachidonoyl glycerol, an endocannabinoid, with 2-palmitoyl glycerol and 2-linoleoyl glycerol, which enhance 2-arachidonoyl glycerol potency, resulted in a significant delay in mortality rates caused by the antagonist. We conclude that the endocannabinoid system plays a vital role in milk suckling, and hence in growth and development during the early stages of mouse life.

Animals↗
PubMed2001

Delta9-tetrahydrocannabinol enhances cortical and hippocampal acetylcholine release in vivo: a microdialysis study.

The intravenous administration of synthetic cannabinoid agonists was recently shown to dose dependently increase acetylcholine release from the rat prefrontal cortex and hippocampus (Eur. J. Pharmacol. 401 (2000) 179]. We report here that the active ingredient of cannabis preparations, delta9-tetrahydrocannabinol, administered at 10, 37.5, 75 and 150 microg/kg, dose dependently stimulated acetylcholine release from rat prefrontal cortex and hippocampus estimated by means of in vivo brain microdialysis with vertical concentric probes. At these doses, delta9-tetrahydrocannabinol induced behavioural stimulation. The administration of the CB1 receptor antagonist, ([N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3carboxamide]HCl) SR 141716A (200 microg/kg i.p.) significantly reduced the effect of delta9-tetrahydrocannabinol (75 microg/kg i.v.) on acetylcholine release from rat prefrontal cortex and hippocampus.

Acetylcholine↗
PubMed2001

Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB(1) receptors.

Activation of peripheral cannabinoid CB(1) receptors elicits hypotension. Using the radioactive microsphere technique, we examined the effects of cannabinoids on systemic hemodynamics in anesthetized rats. The potent cannabinoid CB(1) receptor agonist HU-210 ([-]-11-OH-Delta(9) tetrahydrocannabinol dimethylheptyl, 10 microg/kg i.v.) reduced mean blood pressure by 57+/-5 mm Hg by decreasing cardiac index from 37+/-1 to 23+/-2 ml/min/100 g (P<0.05) without significantly affecting systemic vascular resistance index. HU-210 elicited a similar decrease in blood pressure following ganglionic blockade and vasopressin infusion. The endogenous cannabinoid anandamide (arachidonyl ethanolamide, 4 mg/kg i.v.) decreased blood pressure by 40+/-7 mm Hg by reducing systemic vascular resistance index from 3.3+/-0.1 to 2.3+/-0.1 mm Hg min/ml/100 g (P<0.05), leaving cardiac index and stroke volume index unchanged. HU-210, anandamide, and its metabolically stable analog, R-methanandamide, lowered vascular resistance primarily in the coronaries and the brain. These vasodilator effects remained unchanged when autoregulation was prevented by maintaining blood pressure through volume replacement, but were prevented by pretreatment with the cannabinoid CB(1) receptor antagonist SR141716A (N-[piperidin-1-yl]-5-[4-chlorophenyl]-1-[2,4-dichlorophenyl]-4-methyl-1H-pyrazole-3-carboxamide HCl; 3 mg/kg i.v.). Only anandamide and R-methanandamide were vasodilators in the mesentery. We conclude that cannabinoids elicit profound coronary and cerebral vasodilation in vivo by direct activation of vascular cannabinoid CB(1) receptors, rather than via autoregulation, a decrease in sympathetic tone or, in the case of anandamide, the action of a non-cannabinoid metabolite. Differences between the hemodynamic profile of various cannabinoids may reflect quantitative differences in cannabinoid CB(1) receptor expression in different tissues and/or the involvement of as-yet-unidentified receptors.

Animals↗
PubMed2001

The cannabinoid CB(1) receptor antagonist SR141716A increases norepinephrine outflow in the rat anterior hypothalamus.

The effects of the selective cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide-hydrochloride (SR141716A) on extracellular concentrations of norepinephrine and 5-hydroxytryptamine (5-HT) were assessed by in vivo microdialysis in the anterior hypothalamus of freely moving rats. SR14716A (0.3, 1, 3 mg/kg, i.p.) dose-dependently increased norepinephrine efflux to about 300% of baseline, without affecting 5-HT levels. This increase in norepinephrine outflow could play an important role in the pharmacological and potentially therapeutic actions of SR141716A.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects.

The cannabinoid CB1 receptor has been shown to be the primary site of action for cannabinoid-induced effects on the central nervous system. Activation of this receptor has proven to dampen neurotransmission and produce an overall reduction in neuronal excitability. Cannabinoid compounds like delta9-tetrahydrocannabinol and cannabidiol have been shown to be anticonvulsant in maximal electroshock, a model of partial seizure with secondary generalization. However, until now, it was unknown if these anticonvulsant effects are mediated by the cannabinoid CB1 receptor. Likewise, (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2), a cannabimimetic compound that has been shown to decrease hyperexcitability in cell culture models via the cannabinoid CB1 receptor, has never been evaluated for anticonvulsant activity in an animal seizure model. We first show that the cannabinoid compounds delta9-tetrahydrocannabinol (ED50 = 42 mg/kg), cannabidiol (ED50 = 80 mg/kg), and WIN 55,212-2 (ED50 = 47 mg/kg) are anticonvulsant in maximal electroshock. We further establish, using the cannabinoid CB1 receptor specific antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) (AD50 = 2.5 mg/kg), that the anticonvulsant effects of delta9-tetrahydrocannabinol and WIN 55,212-2 are cannabinoid CB1 receptor-mediated while the anticonvulsant activity of cannabidiol is not. This study establishes a role for the cannabinoid CB1 receptor in modulating seizure activity in a whole animal model.

Animals↗