title: Anti-inflammatory properties of CB1-receptor antagonist involves beta2 adrenoceptors.
abstract: Antagonists of the cannabinoid receptor 1 (CB1) impart anti-inflammatory activity even though, paradoxically, CB2 receptors are more predominant on cells of the immune system. We attempted to understand the mechanism of this activity by using an acute model of lipopolysaccharide-induced inflammation/stress in both rat and mouse, with selective antagonists to CB1 receptors. We demonstrate that the ability of a CB1 antagonist to inhibit release of proinflammatory cytokines is not dependent on either adrenal-derived catecholamines or corticosteroids or input from the pituitary or thymus glands but does involve the spleen. Furthermore, we show that the anti-inflammatory activity is retained without communication from the central nervous system following ganglionic blockade, suggesting a peripheral site of action. Finally, we show that the anti-inflammatory activity can be inhibited with the use of a selective beta2-adrenoceptor antagonist.
authors.affiliation: Pfizer Global Research and Development, Chesterfield, Missouri 63017, USA. stephen.j.mnich@pfizer.com
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Mnich
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Hiebsch
authors.forename: Rita M
authors.initials: RM
authors.lastname: Huff
authors.forename: Shanmugam
authors.initials: S
authors.lastname: Muthian
mesh_terms: D000315:Adrenalectomy; D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D048588:Benzoxazines / Q000494:pharmacology; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D000893:Anti-Inflammatory Agents; D048588:Benzoxazines; C543264:Cnr1 protein, rat; D008070:Lipopolysaccharides; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D018343:Receptors, Adrenergic, beta-2; D014409:Tumor Necrosis Factor-alpha; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone