The effect of cannabinoids on the induction of cytokine mRNA by rat microglial cells was examined. Exposure of neonatal rat cortical microglial cells to the exogenous cannabinoid δ9‐tetrahydrocannabinol (THC) resulted in reduced amounts of lipopolysaccharide (LPS)‐induced mRNAs for IL‐1α, IL‐1β, IL‐6, and TNF‐α. Of these cytokine mRNAs, the response of that for IL‐6 was exquisitely sensitive to THC. Similarly, exposure of microglial cells to the putative endogenous cannabinoid anandamide before LPS treatment resulted in a decrease in cytokine mRNA levels, but not to the same extent as that caused by THC; however, when methanandamide, the non‐hydrolyzable 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 inhibition of LPS‐induced cytokine mRNA expression. A comparable inhibitory outcome was obtained when the paired enantiomers levonantradol and dextronantradol were employed. Neither the CB1‐selective antagonist SR141716A nor the CB2‐selective antagonist SR144528 was able to reverse the inhibition of cytokine mRNA expression by levonantradol. The CB2 antagonist, however, when administered alone augmented the production of cytokine mRNAs. Collectively, these studies demonstrate that cannabinoids can modulate levels of cytokine mRNA in rat microglial cells; however, the inhibition of cytokine mRNA expression is apparently not mediated through either the CB1 or CB2 cannabinoid receptors. GLIA 29:58–69, 2000. © 2000 Wiley‐Liss, Inc.

The effect of cannabinoids on the induction of cytokine mRNA by rat microglial cells was examined. Exposure of neonatal rat cortical microglial cells to the exogenous cannabinoid delta(9)-tetrahydrocannabinol (THC) resulted in reduced amounts of lipopolysaccharide (LPS)-induced mRNAs for IL-1alpha, IL-1beta, IL-6, and TNF-alpha. Of these cytokine mRNAs, the response of that for IL-6 was exquisitely sensitive to THC. Similarly, exposure of microglial cells to the putative endogenous cannabinoid anandamide before LPS treatment resulted in a decrease in cytokine mRNA levels, but not to the same extent as that caused by THC; however, when methanandamide, the non-hydrolyzable 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 inhibition of LPS-induced cytokine mRNA expression. A comparable inhibitory outcome was obtained when the paired enantiomers levonantradol and dextronantradol were employed. Neither the CB(1)-selective antagonist SR141716A nor the CB(2)-selective antagonist SR144528 was able to reverse the inhibition of cytokine mRNA expression by levonantradol. The CB(2) antagonist, however, when administered alone augmented the production of cytokine mRNAs. Collectively, these studies demonstrate that cannabinoids can modulate levels of cytokine mRNA in rat microglial cells; however, the inhibition of cytokine mRNA expression is apparently not mediated through either the CB(1) or CB(2) cannabinoid receptors.