sr-144528 and Endotoxemia

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.

Topics: Animals; Benzoxazines; Camphanes; Cannabinoids; Cytokines; Dose-Response Relationship, Drug; Dronabinol; Endotoxemia; Endotoxins; Injections, Intraperitoneal; Injections, Intravenous; Injections, Intraventricular; Interleukin-10; Interleukin-12; Ligands; Male; Mice; Mice, Knockout; Morpholines; Naphthalenes; Piperidines; Propionibacterium acnes; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Survival Rate; Tumor Necrosis Factor-alpha; Virulence Factors, Bordetella

Previous studies have shown that mice primed with Corynebacterium parvum produce higher levels of inflammatory cytokines than unprimed mice upon challenge with lipopolysaccharide (LPS). Herein, we describe experiments in which two cannabinoid (CB) agonists, WIN 55212-2 [(R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]1, 4-benzoxazin-6-yl](1-naphthyl)methanone) and HU-210 [(-)-11-hydroxy-delta(8) tetrahydrocannabinol-dimethylheptyl], were examined for their effects on LPS-induced cytokines in C. parvum-primed and unprimed mice. These agonists have been reported to bind selectively to the CB2 and CB1 receptor subtypes, respectively. WIN 55212-2 (3.1-50 mg/kg i.p.) and HU-210 (0.05-0.4 mg/kg i.p.) decreased serum tumor necrosis factor-alpha and interleukin-12 (IL-12) and increased IL-10 when administered to mice before LPS. The drugs also protected C. parvum mice (but not unprimed mice) against the lethal effects of LPS. The protection afforded to C. parvum mice could not be attributed to the higher levels of IL-10 present in these mice after agonist treatment. The WIN 55212-2- and HU-210-mediated changes in the responsiveness of mice to LPS were antagonized by SR141716A [N-(piperdin-1-yl)-5-(4-chloropheny)-1-(2, 4-dichloropheny)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride], a selective CB1 receptor antagonist, but not by SR144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2. 1]heptan-2-yl]5-(4-choro-3-methylphenyl)-1-(4-methylbenzyl)p yrazole-3 -carboxamide], a selective antagonist at the CB2 receptor. Therefore, both CB agonists modulated LPS responses through the CB1 receptor. Surprisingly, SR141716A itself modulated cytokine responses in a manner identical with that of WIN 55212-2 and HU-210 when administered alone to mice. The agonist-like effects of SR141716A, which were more striking in unprimed than in primed mice, suggested that the antagonist also could function as a partial agonist at the CB1 receptor. Our findings indicate a role for the CB1 receptor subtype in cytokine modulation by CB ligands.

Topics: Animals; Benzoxazines; Camphanes; Cannabinoids; Cytokines; Dronabinol; Endotoxemia; Endotoxins; Interleukin-10; Interleukin-12; Interleukin-2; Ligands; Lipopolysaccharides; Male; Mice; Morpholines; Naphthalenes; Piperidines; Propionibacterium acnes; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Tumor Necrosis Factor-alpha