The study investigates the role of 2-arachidonoylglycerol (2-AG) in cannabinoid signaling and behavior. The researchers developed a potent and selective inhibitor of monoacylglycerol lipase (MAGL), JZL184, which blocks the hydrolysis of 2-AG but not anandamide. Administration of JZL184 to mice resulted in a significant increase in brain 2-AG levels without altering anandamide levels. Mice treated with JZL184 exhibited a range of cannabinoid-dependent behavioral effects, including analgesia, hypothermia, and hypomotility. These findings suggest that 2-AG modulates several behavioral processes associated with cannabinoid pharmacology and highlight the distinct and overlapping functions of 2-AG and anandamide in vivo. The study also discusses the therapeutic implications of these findings and the potential for dual inhibitors of MAGL and fatty acid amide hydrolase (FAAH) to target both endocannabinoids.The study investigates the role of 2-arachidonoylglycerol (2-AG) in cannabinoid signaling and behavior. The researchers developed a potent and selective inhibitor of monoacylglycerol lipase (MAGL), JZL184, which blocks the hydrolysis of 2-AG but not anandamide. Administration of JZL184 to mice resulted in a significant increase in brain 2-AG levels without altering anandamide levels. Mice treated with JZL184 exhibited a range of cannabinoid-dependent behavioral effects, including analgesia, hypothermia, and hypomotility. These findings suggest that 2-AG modulates several behavioral processes associated with cannabinoid pharmacology and highlight the distinct and overlapping functions of 2-AG and anandamide in vivo. The study also discusses the therapeutic implications of these findings and the potential for dual inhibitors of MAGL and fatty acid amide hydrolase (FAAH) to target both endocannabinoids.