Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells

The effect of cannabinoids on the induction of cytokine mRNA by rat microgl ial cells was examined. Exposure of neonatal rat cortical microglial cells to the exogenous cannabinoid delta(9)-tetrahydrocannabinol (THC) resulted i n reduced amounts of lipopolysaccharide (LPS)-induced mRNAs for IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha. Of these cytokine mRNAs, the response of t hat for IL-6 was exquisitely sensitive to THC. Similarly, exposure of micro glial cells to the putative endogenous cannabinoid anandamide before LPS tr eatment resulted in a decrease in cytokine mRNA levels, but not to the same extent as that caused by THC; however, when methanandamide, the nonhydroly zable analog of anandamide was tested, its ability to inhibit cytokine mRNA expression was comparable to that of THC. Exposure of microglial cells to either of the paired enantiomers CP55,940 or CP56,667 resulted in similar i nhibition of LPS-induced cytokine mRNA expression. A comparable inhibitory outcome was obtained when the paired enantiomers levonantradol and dextrona ntradol were employed. Neither the CB1-selective antagonist SR141716A nor t he CB2-selective antagonist SR144528 was able to reverse the inhibition of cytokine mRNA expression by levonantradol. The CB2 antagonist, however, whe n administered alone augmented the production of cytokine mRNAs. Collective ly, these studies demonstrate that cannabinoids can modulate levels of cyto kine mRNA in rat microglial cells; however, the inhibition of cytokine mRNA expression is apparently not mediated through either the CBL or CB2 cannab inoid receptors. GLIA 29:58-65 2000. (C) 2000 Wiley-Liss, Inc.