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PubMed2001

Modulation of cytokine responses in Corynebacterium parvum-primed endotoxemic mice by centrally administered cannabinoid ligands.

The cannabinoid receptor agonists [(-)-11-hydoxy-Delta(8)tetrahydrocannabinol-dimethylheptyl] (HU-210) and [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl[pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthalenyl) methanone] (WIN 55212-2) were previously shown to downregulate inflammatory cytokines (tumor necrosis factor alpha and interleukin-12) and to upregulate antiinflammatory interleukin-10 when administered intraperitoneally (i.p.) to mice before an endotoxin challenge. Cytokine modulation coincided with the onset of behavioral changes that are associated with cannabinoid agonist activated central cannabinoid CB(1) receptors. Both effects were antagonized by [N-(piperdin-1-yl)-5-(4-chloropheny)-1-(2,4-dichloropheny)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] (SR141716A) a selective cannabinoid CB(1) receptor antagonist. In the present study, we have investigated further the apparent role of central CB(1) cannabinoid receptors in cytokine modulation by HU-210 and WIN 55212-2. When administered intracerebroventricularly (i.c.v.), the drugs modulated cytokine responses at doses that were threefold to fourfold lower than those found effective by the i.p. route. SR141716A blocked cytokine modulation when coadministered centrally with the agonists, while a selective cannabinoid CB(2) receptor antagonist, (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]5-(4-choro-3 methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide) (SR144528) had no effect. Surprisingly, SR144528 was found to modulate cytokines itself when injected i.c.v.

Animals↗
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↗
PubMed2001

The cannabinoid CB1 receptor antagonist SR 141716A reverses the antiemetic and motor depressant actions of WIN 55, 212-2.

The dibenzopyran cannabinoids (delta-9 (Delta9)-tetrahydrocannabinol and nabilone) are clinically used to suppress nausea and vomiting produced by chemotherapeutic agents such as cisplatin. The purpose of this investigation was to investigate the antiemetic potential of the aminoalkylindole cannabinoid receptor agonist WIN 55, 212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl) methyl] pyrolol [1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate] against cisplatin-induced vomiting. Different doses of WIN 55, 212-2 (0, 1, 2.5 and 5 mg/kg, i.p.) reduced both the frequency of cisplatin (20 mg/kg, i.p.)-induced emesis (ID(50)=0.5 mg/kg) as well as the percentage of shrews vomiting (ID50=1.2 mg/kg) in a dose-dependent manner. Significant reductions in emesis frequency occurred from 2.5 mg/kg dose of WIN 55, 212-2, whereas significant total protection from vomiting was afforded at its 5 mg/kg dose. The antiemetic actions of a 5-mg/kg dose of WIN 55, 212-2 against cisplatin (20 mg/kg, i.p.)-induced vomiting were reversed by nonemetic subcutaneous doses (0, 0.25, 0.5 and 1 mg/kg) of the cannabinoid CB1 receptor antagonist/inverse agonist SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] (ID50=0.27 and 0.47 mg/kg, respectively) but not by a 5-mg/kg dose of the cannabinoid CB2 receptor antagonist SR 144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1] heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4-methybenzyl) pyrazole-3-carboxamide]. The effects of the cited doses of WIN 55, 212-2 were also investigated on several motor parameters (spontaneous locomotor activity, duration of movement and rearing frequency). Significant reductions in motor parameters were only observed at its highest tested dose (ID50=1.97, 2.75 and 2.8 mg/kg; respectively). SR 141716A (0, 0.5, 1, 5 and 10 mg/kg) also reversed the motor suppressant effects of a 5-mg/kg dose of WIN 55, 212-2 (ID50=0.39, 0.1 and 0.3 mg/kg, respectively) and significant reversals were seen from its 0.5 and 1 mg/kg doses. These results suggest that WIN 55, 212-2 reduces both emesis and indeces of locomotion via the stimulation of cannabinoid CB1 receptors. However, cannabinoid CB1 receptors in different loci are most likely responsible for the antiemetic and motor suppressive effects of WIN 55, 212-2 since reduction in the frequency of vomiting occurred at lower doses relative to its sedative actions.

Animals↗
PubMed2001

The anti-inflammatory activities of cannabinoid receptor ligands in mouse peritonitis models.

In this report, we describe experiments in which cannabinoid receptor ligands were evaluated for effects on the development of a peritoneal inflammation when elicited in mice with thioglycollate broth or staphylococcus enterotoxin A. The cannabinoid receptor agonists [(-)-11-hydoxy-Delta(8) tetrahydrocannabinol-dimethylheptyl] (HU-210) and [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl[pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthalenyl) methanone] (WIN 55212-2) blocked the migration of neutrophils into the peritoneal cavity in response to these inflammatory stimuli. This effect was caused by a delay in the production of the neutrophil chemoattractants, KC and macrophage inflammatory protein-2. HU-210 and WIN 55212-2 blocked neutrophil chemokines and neutrophil migration whether administered subcutaneously (s.c.) or intracerebroventricularly (i.c.v.). Their modulatory effects on the inflammation were antagonized by centrally administered [N-(piperdin-1-yl)-5-(4-chloropheny)-1-(2,4-dichloropheny)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] (SR141716A), a selective cannabinoid CB(1) receptor antagonist. This latter observation, and the ability of the cannabinoid receptor agonists to suppress the peritoneal inflammation at relatively low doses when administered i.c.v., indicated a role for central cannabinoid CB(1) receptors in the anti-inflammatory activities of HU-210 and WIN 55212-2. The cannabinoid receptor agonists had no effect on monocyte migration elicited by thioglycollate, despite their ability to suppress monocyte chemotactic protein-1 levels in lavage fluids. The cannabinoid CB(2) receptor antagonist, [N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]5-(4-choro-3 methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide] (SR144528) inhibited the peritoneal inflammation in a manner analogous to that of HU-210 and WIN 55212-2 when administered i.c.v., but it did not appear to act through central cannabinoid CB(1) receptors. The present results add to the body of literature indicating that cannabinoid receptor ligands have diverse anti-inflammatory properties.

Animals↗
PubMed2002

Effect of cannabinoids on synaptic transmission in the rat hippocampal slice is temperature-dependent.

We have previously reported that the synthetic cannabinoid R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2) causes a selective inhibition of paired pulse depression of population spikes recorded from the CA1 region of rat hippocampal slices maintained at 28-30 degrees C. We now show that this effect is highly temperature-dependent and that WIN55,212-2 actually increases paired pulse depression of population spikes recorded from slices maintained at 35 degrees C. This temperature dependence was found to correlate with the effects of the known gamma-amino butyric acid (GABA)-uptake inhibitors, nipecotic acid and guvacine, which were without effect at 28-30 degrees C, but increased paired pulse depression at 35 degrees C. The results show that the effects of cannabinoids on synaptic transmission in the hippocampal slice are highly temperature-dependent and it is suggested that this is due to the presence of increased GABA uptake at higher temperatures.

Animals↗
PubMed2002

Cannabinoid receptor antagonism and inverse agonism in response to SR141716A on cAMP production in human and rat brain.

The effects of cannabinoid drugs on cAMP production were examined in mammalian brain. The cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3,-d,e-1,4-benzoxazin-6-yl]-(1-naphthalenyl) methanone (WIN55,212-2) decreased forskolin-induced cAMP accumulation in a concentration-dependent manner (10(-8)-10(-5) M) in membranes from several rat and human brain regions, this effect being antagonized by 10(-5) M N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A). Furthermore, high micromolar concentrations of SR141716A evoked a dose-dependent increase in basal cAMP in rat cerebellum and cortex, as well as in human frontal cortex. This effect was antagonized by WIN55,212-2 and abolished by N-ethylmaleimide, consistent with the involvement of cannabinoid CB(1) receptors through the activation of G(i/o) proteins. These results suggest a ligand-independent activity for cannabinoid CB(1) receptor signaling cascade in mammalian brain.

Animals↗
PubMed2002

Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB(1) receptors.

We studied the delay in gastric emptying and gastrointestinal transit induced by the cannabinoid receptor agonists (+)-WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate) and CP 55,940 ((-)-cis-3[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol), as prevented by the selective cannabinoid CB(1)-receptor antagonist SR141716 ((N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide)) in rats after systemic or central drug administration. Oral SR141716 showed comparable potency (ID(50) range 1.0-3.9 mg/kg) in antagonizing gastric emptying and gastrointestinal transit delay by (+)-WIN 55,212-2 or CP 55,940. Gastric emptying and gastrointestinal transit delay after intracerebroventricular (i.c.v.) (+)-WIN 55,212-2 was prevented by oral or i.c.v. SR141716, but i.c.v. SR141716 did not significantly reduce the effect of i.p. (+)-WIN 55,212-2. Pertussis toxin prevented the delaying action of i.c.v. (+)-WIN 55,212-2 on both gastric emptying and gastrointestinal transit, but had no effect on (+)-WIN 55,212-2 i.p. These findings are consistent with a primary role of peripheral cannabinoid CB(1) receptor mechanisms in gastrointestinal transit delay by specific agonists.

Administration, Oral↗
PubMed2002

Effects of Win 55,212-2 on hippocampal CA1 long-term potentiation in experiments controlled for basal glutamatergic synaptic transmission.

Cannabinoids, the active components of marijuana, are presumed to affect memory by an action on long-term potentiation. However, these molecules also reduce hippocampal glutamatergic neurotransmission. To distinguish the two activities, we studied the effects of the synthetic cannabinoid (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtalenylmethanone (Win 55,212-2, 10 microM) on CA1 hippocampal responses generated by the activation of two independent pathways, one of which was potentiated with a tetanic stimulation. The results of the study show the following: (a) the drug does not affect long-term potentiation provided that the responses are compared to those obtained in the unpotentiated control pathway; (b) Win 55,212-2 increases post-tetanic potentiation.

Animals↗
PubMed2002

(-)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens.

The nonpsychoactive plant cannabinoid, (-)-cannabidiol, modulates in vivo responses to Delta(9)-tetrahydrocannabinol. We have found that cannabidiol can also interact with cannabinoid CB(1) receptor agonists in the mouse vas deferens, a tissue in which prejunctional cannabinoid CB(1) receptors mediate inhibition of electrically evoked contractions by suppressing noradrenaline and/or ATP release. Cannabidiol (0.316-10 microM) attenuated the ability of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) to inhibit contractions in a concentration-related, surmountable manner with a K(B) value (120.3 nM) well below its reported cannabinoid receptor CB(1)/CB(2) K(i) values. Cannabidiol (10 microM) also antagonized (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940; K(B)=34 nM) and [D-Ala(2), NMePhe(4), Gly-ol]enkephalin (DAMGO; K(B)=5.6 microM) and attenuated contractile responses to noradrenaline, phenylephrine and methoxamine but not to beta, gamma-methyleneadenosine 5'-triphosphate. At 3.16-10 microM, it increased the amplitude of evoked contractions, probably by enhancing contractile neurotransmitter release. We conclude that cannabidiol antagonizes R-(+)-WIN55212 and CP55940 by acting at prejunctional sites that are unlikely to be cannabinoid CB(1) or CB(2) receptors.

Adenosine Triphosphate↗
PubMed2003

Antiemetic and motor-depressive actions of CP55,940: cannabinoid CB1 receptor characterization, distribution, and G-protein activation.

Dibenzopyran (Delta(9)-tetrahydrocannabinol) and aminoalkylindole [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate; (WIN55,212-2)] cannabinoids suppress vomiting produced by cisplatin via cannabinoid CB(1) receptors. This study investigates the antiemetic potential of the "nonclassical" cannabinoid CP55,940 [1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol] against cisplatin-induced vomiting and assesses the presence and functionality of cannabinoid CB(1) receptors in the least shrew (Cryptotis parva) brain. CP55,940 (0.025-0.3 mg/kg) reduced both the frequency of cisplatin-induced emesis (ID(50)=0.025 mg/kg) and the percentage of shrews vomiting (ID(50)=0.09 mg/kg). CP55,940 also suppressed shrew motor behaviors (ID(50)=0.06- 0.21 mg/kg) at such doses. The antiemetic and motor-suppressant actions of CP55,940 were countered by SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], indicating both effects are cannabinoid CB(1) receptor-mediated. Autoradiographic studies with [3H]-SR141716A and [35S]-GTPgammaS binding revealed that the distribution of the cannabinoid CB(1) receptor and its activation pattern are similar to rodent brain and significant levels are present in brain loci (e.g., nucleus tractus solitarius (NTS)) that control emesis. The affinity rank order of structurally diverse cannabinoid ligands for cannabinoid CB(1) receptor in shrew brain is similar to rodent brain: HU-210=CP55,940=SR141716A>/=WIN55,212-2>/=delta-9-tetrahydrocannabinol>methanandamide=HU-211=cannabidiol=2-arachidonoylglycerol. This affinity order is also similar and is highly correlated to the cannabinoid EC(50) potency rank order for GTPgammaS stimulation except WIN55,212-2 and delta-9-tetrahydrocannabinol potency order were reversed. The affinity and the potency rank order of tested cannabinoids were significantly correlated with their antiemetic ID(50) potency order against cisplatin-induced vomiting (CP55,940>WIN55,212-2=delta-9-tetrahydrocannabinol) as well as emesis produced by 2-arachidonoylglycerol or SR141716A (CP55,940>WIN55,212-2>delta-9-tetrahydrocannabinol).

Animals↗
PubMed2003

R+-methanandamide inhibits tracheal response to endogenously released acetylcholine via capsazepine-sensitive receptors.

The effects of cannabinoid drugs on the cholinergic response evoked by electrical field stimulation (0.2 ms pulse width, 20 V amplitude, 10 Hz, 7.5 s train duration) in guinea-pig tracheal preparations were investigated. The stable analogue of the endocannabinoid anandamide, R(+)-methanandamide (10(-7)-10(-4) M), produced a dose-dependent inhibition (up to 27+/-5% of control) of electrical field stimulation-mediated atropine-sensitive response. This effect was not blocked by 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 (SR 141716A; 10(-6) M), and was not reproduced with the cannabinoid CB(1)/CB(2) receptor agonist R(+)-[2,3-dihydro-5-methyl-[(morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate) (WIN 55,212-2; 10(-8)-10(-5) M) or the cannabinoid CB(2) receptor selective agonist 1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015; 10(-8)-10(-5) M); it was, on the contrary, antagonized by the vanilloid antagonist 2-[2-(4-chlorophenyl)ethyl-amino-thiocarbonyl]-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-2 benzazepine (capsazepine; 10(-6) M). At the postjunctional level, neither R(+)-methanandamide nor WIN 55,212-2 nor JWH-015 did affect tracheal contractions induced by exogenous acetylcholine (10(-6) M). An inhibitory vanilloid receptor-mediated effect on the cholinergic response evoked by electrical stimulation was confirmed with the vanilloid agonist capsaicin, at doses (3-6 x 10(-8) M) which poorly influenced the basal smooth muscle tone of trachea. In conclusion, our data indicate that in guinea-pig trachea (a) neither CB(1) nor CB(2) cannabinoid receptor-mediated modulation of acetylcholine release occurs; (b) vanilloid VR1-like receptors appear involved in R(+)-methanandamide inhibitory activity on the cholinergic response to electrical field stimulation.

Acetylcholine↗
PubMed2003

Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice: evidence for a "CB3" receptor.

Cannabinoids, whether plant-derived, synthetic or endogenous, have been shown to stimulate appetite in the adult organism. We have reported previously that cannabinoid receptors play a critical role during the early suckling period: The selective cannabinoid CB(1) receptor antagonist N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141617A) permanently prevented milk ingestion in a dose-dependent manner, when administered to (Sabra, albino) mouse pups, within 1 day of birth. As a consequence, these pups died within the first week of life. We now generalize this finding to a different strain of mice (C57BL/6). Further, we show that cannabinoid CB(1) receptor blockade (20 mg/kg SR141716A) must occur within 24 h after birth as injection of SR141716A into 2- or 5-day-old pups had a much smaller effect or no effect at all, respectively. Cannabinoid CB(1) receptor knockout mice did not ingest milk on the first day of life, similarly to SR141716A-treated normal pups, as measured by the appearance of "milkbands". However, the knockout pups started to display milkbands from day 2 of life. Survival rates of cannabinoid CB(1) receptor knockout mice were affected significantly, but to a lesser extent than normal pups, by the administration of SR141716A. Daily administration of the endocannabinoid 2-arachidonoyl glycerol, or the synthetic agonists (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2, 5 mg/kg) or (-)-cis-3-[2-Hydroxy4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940, 5 or 20 mg/kg) did not promote survival or weight gain in CB(1)(-/-) pups. Our data support previous evidence for a critical role of cannabinoid CB(1) receptors for the initiation of suckling. Further, the present observations support the existence of an unknown cannabinoid receptor, with partial control over milk ingestion in newborns. Our data also suggest that the CB(1)(-/-) neonates possess a compensatory mechanism which helps them overcome the lack of cannabinoid CB(1) receptors.

Animals↗
PubMed2003

Pharmacological characterisation of cannabinoid receptors inhibiting interleukin 2 release from human peripheral blood mononuclear cells.

The effects of a range of cannabinoid receptor agonists and antagonists on phytohaemagglutinin-induced secretion of interleukin-2 from human peripheral blood mononuclear cells were investigated. The nonselective cannabinoid receptor agonist WIN55212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate) and the selective cannabinoid CB(2) receptor agonist JWH 015 ((2-methyl-1-propyl-1H-indol-3-yl)-1-napthalenylmethanone) inhibited phytohaemagglutinin (10 microg/ml)-induced release of interleukin-2 in a concentration-dependent manner (IC(1/2max), WIN55212-2=8.8 x 10(-7) M, 95% confidence limits (C.L.)=2.2 x 10(-7)-3.5 x 10(-6) M; JWH 015=1.8 x 10(-6) M, 95% C.L.=1.2 x 10(-6)-2.9 x 10(-6) M, n=5). The nonselective cannabinoid receptor agonists CP55,940 ((-)-3-[2-hydroxy-4-(1,1-dimethyl-hepthyl)-phenyl]4-[3-hydroxypropyl]cyclo-hexan-1-ol), Delta(9)-tetrahydrocannabinol and the selective cannabinoid CB(1) receptor agonist ACEA (arachidonoyl-2-chloroethylamide) had no significant (P>0.05) inhibitory effect on phytohaemagglutinin-induced release of interleukin-2. Dexamethasone significantly (P<0.05) inhibited phytohaemagglutinin-induced release of interleukin-2 in a concentration-dependent manner (IC(1/2max)=1.3 x 10(-8) M, 95% C.L.=1.4 x 10(-9)-3.2 x 10(-8) M). The cannabinoid CB(1) receptor antagonist SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride) (10(-6) M) did not antagonise the inhibitory effect of WIN55212-2 whereas the cannabinoid CB(2) receptor antagonist SR144528 (N-(1,S)-endo-1,3,3-trimethyl bicyclo(2,2,1)heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) antagonised the inhibitory effect of WIN55212-2 (pA(2)=6.3+/-0.1, n=5). In addition, CP55,940 (10(-6) M) and Delta(9)-tetrahydrocannabinol (10(-6) M) also antagonised the inhibitory effects of WIN55212-2 (pA(2)=6.1+/-0.1, n=5 and pA(2)=6.9+/-0.2, n=5). In summary, WIN55,212-2 and JWH 015 inhibited interleukin-2 release from human peripheral blood mononuclear cells via the cannabinoid CB(2) receptor. In contrast, CP55,940 and Delta(9)-tetrahydrocannabinol behaved as partial agonists/antagonists in these cells.

Arachidonic Acids↗
PubMed2003

Cannabinoid CB1 receptor-mediated inhibition of glutamate release from rat hippocampal synaptosomes.

Cannabinoid receptors are widely expressed in the brain and have been shown to regulate synaptic transmission through a presynaptic mechanism. Using synaptosomal preparation, I show here that 2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl)-pyrrolo-1,4-benzoxazin-6-yl-1-naphthalenylmethanone (WIN 55212-2) strongly depressed 4-aminopyridine-evoked glutamate release in a concentration-dependent manner, and this effect was reversed by the selective cannabinoid CB(1) receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM 281). The inhibitory modulation by WIN 55212-2 was not due to a decrease in synaptosomal excitability or a direct effect on the release machinery because WIN 55212-2 did not alter 4-aminopyridine-mediated depolarization and ionomycin-induced glutamate release. In addition, the WIN 55212-2-mediated inhibition of glutamate release was blocked by the G(i)/G(o) protein inhibitor pertussis toxin, but not by the protein kinase A inhibitor 2,3,9,10,11,12-Hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo-benzodiazocine-10-carboxylic acid, hexyl ester (KT 5720). Furthermore, this inhibitory effect was associated with a decrease in 4-aminopyridine-evoked Ca(2+) influx, which could be completely prevented in synaptosomes pretreated with the N- and P/Q-type Ca(2+) channel blockers. Together, these observations indicate that activation of cannabinoid CB(1) receptors inhibit 4-aminopyridie-evoked glutamate release from hippocampal synaptosomes through a inhibitory G protein to suppress N- and P/Q-type Ca(2+) channel activity.

Animals↗
PubMed2003

Antitussive effect of WIN 55212-2, a cannabinoid receptor agonist.

Several lines of evidence indicate that the opioid and cannabinoid systems produce synergistic interactions. The present study examined the opioid receptors involved in the antitussive effect of WIN 55212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate), a high-affinity cannabinoid receptor agonist, in mice. WIN 55212-2, at doses of 0.3-3 mg/kg ip, produced a dose-dependent antitussive effect. This antitussive effect of WIN 55212-2 was antagonized by pretreatment with either methysergide (3 mg/kg ip), a 5-HT receptor antagonist, or naloxone (1 mg/kg ip), an opioid receptor antagonist. Furthermore, pretreatment with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 3 mg/kg ip), a cannabinoid CB(1) receptor antagonist, also significantly reduced the antitussive effect of WIN 55212-2. Blockade of mu-opioid receptors by pretreatment with beta-funaltrexamine (40 mg/kg sc) significantly reduced the antitussive effect of WIN 55212-2. However, pretreatment with nor-binaltorphimine (20 mg/kg sc), a kappa-opioid receptor antagonist, did not affect the antitussive effect of WIN 55212-2. Pretreatment with naloxonazine (35 mg/kg sc), a mu(1)-opioid receptor antagonist, also did not affect the antitussive effect of WIN 55212-2. These results indicate that the antitussive effect of WIN 55212-2 is mediated by the activation of cannabinoid CB(1) receptors and mu(2) (naloxonazine-insensitive)-opioid receptors, but not mu(1) (naloxonazine-sensitive)- or kappa-opioid receptors.

Animals↗
PubMed2003

Effects of cannabinoids on non-adrenergic non-cholinergic-mediated relaxation in guinea-pig trachea.

The effects of cannabinoid receptor agonists on the non-adrenergic non-cholinergic (NANC) inhibitory responses to electrical field stimulation in guinea-pig trachea were assessed. R-(+)-[2,3-dihydro-5-methyl-3-[(morpholilinyl) methyl]pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate (WIN 55,212-2; 10(-5) M) significantly enhanced the frequency-dependent response to electrical stimulation. The same concentration of R-(N)-(2-hydroxy-1-methylethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (R(+)methanandamide) and 1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015) did not affect significantly the electrically induced inhibitory NANC responses. The effect of WIN 55,212-2 was not modified by the cannabinoid CB1 and CB2 receptor-selective antagonists, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A; 10(-5) M) and N-(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR 144528; 10(-5) M), respectively. Moreover, the nitric oxide synthase inhibitor, L-NG-nitro-arginine methyl ester (L-NAME; 10(-4) M), but not the peptidase, alpha-chymotrypsin (2 U/ml), blocked the effect of WIN 55,212-2. Postsynaptically, WIN 55,212-2 did not produce any change of tracheal smooth muscle tone, either basal or histamine-induced, and did not interfere with the relaxant activity of the nitric oxide donor, sodium nitroprusside (10(-8)-10(-4) M). In conclusion, our results suggest that (a) cannabinoid CB1 and CB2 receptor stimulation does not alter the inhibitory NANC transmission in guinea-pig trachea, and (b) WIN 55,212-2 potentiates the NO-mediated component of the NANC relaxant response to electrical stimulation through a cannabinoid receptor-independent mechanism.

Animals↗
PubMed1996

Agonist-antagonist characterization of 6'-cyanohex-2'-yne-delta 8-tetrahydrocannabinol in two isolated tissue preparations.

This investigation was directed at characterizing some of the pharmacological properties of 6'-cyanohex-2'-yne-delta 8-tetrahydrocannabinol (O-823), a compound with high affinity for cannabinoid binding sites (Ki = 0.77 nM). In mouse vasa deferentia, O-823 behaved as a potent partial cannabinoid CB1 receptor agonist (EC50 = 0.015 nM). In the guinea-pig myenteric plexus preparation, it antagonized WIN 55.212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholino)methyl]pyrrolo-[1,2,3-de ]-1, 4-benzoxazin-6-yl](1-naphthyl)methanone] and CP 55.940 [(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl ) cyclohexan-1-ol] with Kd values of 0.65 and 0.27 nM, respectively. After in vivo delta 9-tetrahydrocannabinol pretreatment. the sensitivity of vasa deferentia to O-823-induced inhibition of electrically evoked contractions was reduced by 127-fold. 3.162 nM O-823 was inhibitory in unpretreated vasa deferentia but antagonized CP 55,940 in pretreated tissues (Kd = 0.26 nM). O-823 is probably an antagonist in the myenteric plexus preparation and delta 9-tetrahydro-cannabinol pretreated vasa deferentia but a partial agonist in unpretreated vasa deferentia because the first two of these preparations contain fewer receptors than the third.

Analgesics↗
PubMed1997

AM630 antagonism of cannabinoid-stimulated [35S]GTP gamma S binding in the mouse brain.

This research was designed to determine the action of the novel aminoalkylindole AM630 (6-iodo-pravadoline) at the cannabinoid receptor by studying its interaction with the cannabinoid receptor agonist WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazin-y]-(1-naphthalenyl)methanone mesylate) on guanosine-5'-O-(3-[35S]thio) triphosphate ([35S]GTP gamma S) binding in mouse brain. WIN 55,212-2 stimulated [35S]GTP gamma S binding, while AM630 had no effect. AM630 antagonized WIN 55,212-2-2induced [35S]GTP gamma S binding and shifted the WIN 55,212-dose-response curve to the right. These results clearly demonstrate that AM630 exerts cannabinoid receptor antagonist properties in the brain.

Analgesics↗