The endocannabinoid lipid 2-arachidonoylglycerol (2-AG) is deactivated by intracellular hydrolysis catalyzed by monoacylglycerol lipase. 2-AG also serves as a substrate for oxidative metabolism catalyzed by cyclooxygenase 2 (COX-2). However, products of COX-2-mediated metabolism of endocannabinoids have not been identified in vivo. Hu and colleagues in this issue of the BJP demonstrate that COX-2 converts 2-AG into a biologically active, pro-nociceptive compound, prostaglandin E2 glycerol ester (PGE2-G). PGE2-G produces hyperalgesia in vivo and activates a rapidly acting transcription factor, nuclear factor kappa-B in vitro. These biological actions may be attributed to a unique receptor. This report of pro-nociceptive actions of an endogenous COX-2 metabolite of 2-AG that are largely opposite to known anti-nociceptive and anti-inflammatory actions of endocannabinoids has physiological relevance. These discoveries place renewed emphasis on the importance of understanding the highly interactive nature of lipid signalling pathways in the nervous system and the physiological roles of these lipid mediators in controlling homeostasis.