Background and purpose: This study determined the effect of JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), the enzyme which preferentially catabolises the endocannabinoid 2-arachidonoyl glycerol (2-AG), on inflammatory cytokines in the brain and plasma following an acute immune challenge. The receptor and molecular mechanisms involved were also investigated.Experimental approach: JZL184 and/or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) were administered to rats 30 min prior to the administration of lipopolysaccharide (LPS), 2hrs following which cytokine expression/levels, MAGL activity, 2-AG, arachidonic acid and prostaglandin levels were measured in the frontal cortex, plasma and spleen.Key Results: JZL184 attenuated LPS-induced increases in IL-1β, IL-6, TNF-α and IL-10, but not IĸBα expression in the rat frontal cortex. AM251 attenuated the JZL184-induced decrease in frontal cortical IL-1β expression. Although arachidonic acid levels in the frontal cortex were reduced in JZL184-treated rats, MAGL activity, 2-AG, PGE2 and PGD2 levels remained unchanged. In comparison, MAGL activity was inhibited and 2-AG levels enhanced in the spleen following JZL184 administration. In the plasma, LPS-induced increases in TNF-α and IL-10 levels were attenuated by JZL184, an effect partially blocked by AM251. In addition, AM630 blocked the LPS-induced increases in plasma IL-1β in the presence, but not absence, of JZL184.Conclusion and Implications: Inhibition of peripheral MAGL in the rat by JZL184 suppresses LPS-induced circulating cytokines which in turn may modulate central cytokine expression. The data provide further evidence for the therapeutic potential of targeting the endocannabinoid system for the treatment of central and peripheral inflammatory disorders.