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.
Smith
S R
SR
Department of Immunology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. sidney.smith@spcorp.com
Denhardt
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G
Terminelli
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D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001202:Ascitic Fluid / Q000737:chemistry / Q000166:cytology; D048588:Benzoxazines; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004768:Enterotoxins / Q000008:administration & dosage; D005260:Female; D005838:Genotype; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015846:Monokines / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D013864:Thioglycolates / Q000008:administration & dosage
D000893:Anti-Inflammatory Agents; D048588:Benzoxazines; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D018925:Chemokines; D004768:Enterotoxins; D008024:Ligands; D015846:Monokines; D009025:Morpholines; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013864:Thioglycolates; C026066:enterotoxin A, Staphylococcal; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C062018:HU 211