Activated brain microglial cells release inflammatory mediators such as nitric oxide (NO) that may play important roles in central nervous system antibacterial, antiviral, and antitumor activities. However, excessive release of these factors has been postulated to elicit immune-mediated neurodegenerative inflammatory processes and to cause brain injury. Recent studies using the rat animal model indicate that select cannabinoids may modulate production of these inflammatory factors. Treatment of neonatal rat brain cortical microglial cells with the cannabinoid paired enantiomers CP55940 and CP56667 resulted in a stereoselective differential effect on inducible NO production. The analog CP55940 exerted a dose-dependent inhibition of interferon gamma (IFNy)/bacterial lipopolysaccharide (LPS)-inducible NO production which was significantly greater than that exerted by CP56667. Pretreatment of microglial cells with the CB1 cannabinoid receptor-selective antagonist SR141716A reversed this CP55940-mediated inhibition. MRT-PCR demonstrated the presence of CB1 receptor mRNA within microglial cells consistent with the presence of CB1 receptors. Collectively, these results indicate that the cannabinoid analog CP55940 selectively inhibits inducible NO production by microglial cells and that this inhibition is effected, at least in part, through the CB1 receptor.