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

The cannabinoid receptor agonists [(-)-11-hydoxy-Delta (8)tetrahydrocannabi nol-dimethytheptyl] (HU-210) and {(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morph olinyl)methyl[pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthalenyl) methano ne} (WIN 55212-2) were previously shown to downregulate inflammatory cytoki nes (tumor necrosis factor alpha and interleukin-12) and to upregulate anti inflammatory interleukin-10 when administered intraperitoneally (i.p.) to m ice before an endotoxin challenge. Cytokine modulation coincided with the o nset of behavioral changes that are associated with cannabinoid agonist act ivated central cannabinoid CB1 receptors. Both effects were antagonized by [N-(piperdin-1-yl)-5-(4-chloropheny)-1-(2,4-dichloropheny)-4-methyl-1H-pyra zole-3-carboxanlide hydrochloride] (SR141716A) a selective cannabinoid CB1 receptor antagonist. In the present study, we have investigated further the apparent role of central CB1 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 t o fourfold lower than those found effective by the i.p. route. SR141716A bl ocked cytokine modulation when coadministered centrally with the agonists, while a selective cannabinoid CB2 receptor antagonist, {N-[(1S)-endo-1,3,3 -trimethylbicyclo[2.2.1]heptan-2-yl]5-(4-choro-3 methylphenyl)-1-(4-methylb enzyl)pyrazole-3-carboxamide} (SR144528) had no effect. Surprisingly, SR144 528 was found to modulate cytokines itself when injected i.c.v. (C) 2001 El sevier Science B.V. All rights reserved.