A Novel Role of Cannabinoids: Implication in the Fever Induced by Bacterial Lipopolysaccharide

Abstract

There is continuing interest in elucidating the actions of drugs of abuse on the immune system and on infection. The present study investigated the effects of the cannabinoid (CB) receptor agonist aminoalkylindole, (+)-WIN 55,212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], on fever produced after injection of lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, the best known and most frequently used experimental model. Intraperitoneal injection of LPS (50 mug/kg) induced a biphasic fever, with the first peak at 180 min and the second at 300 min postinjection. Pretreatment with a nonhypothermic dose of the cannabinoid receptor agonist WIN 55,212-2 (0.5-1.5 mg/kg i.p.) antagonized the LPS-induced fever. However, pretreatment with the inactive enantiomer WIN 55,212-3 [1.5 mg/kg i.p.; S-(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthanlenyl)methanone mesylate] did not. The inhibitory effect of WIN 55,212-2 on LPS-induced fever was reversed by SR141716 [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)pyrazole-3-carboxamide), a selective antagonist at the CB2 receptor. The present results show that cannabinoids interact with systemic bacterial LPS injection and indicate a role of the CB1 receptor subtype in the pathogenesis of LPS fever.