This study investigated cannabinoid receptor-mediated regulation of brain and peripheral cytokines in vivo. The cannabinoid receptor agonist, HU210 attenuated lipopolysaccharide (LPS)-induced increases in IL-1 beta and TNF alpha in rat brain and IL-1 beta, TNF alpha, IL-6 and IFN gamma in plasma. The CB1 receptor antagonist, SR141716A, attenuated the immunosupressive effects of HU210 on IL-1 beta, but not TNF alpha. SR141716A or the CB2 receptor antagonist, SR144528, alone attenuated LPS-induced cytokine increases. LPS and/or cannabinoids also reduced circulating lymphocyte numbers and increased corticosterone levels. These data provide evidence for modulation of pro-inflammatory cytokines in vivo by cannabinoid receptors and inform the development of cannabinoids for neuroinflammatory disorders. (c) 2006 Elsevier B.V. All rights reserved.