BACKGROUND: Propofol can inhibit fatty acid amidohydrolase, the enzyme responsible for the metabolism of anandamide (an endocannabinoid). To study the potential antinociceptive effect of propofol, we administered different doses (0.005, 0.05, 0.5, 5, and 500 μg) of the anesthetic in the hind paw of animals to determine an ED50. To further investigate the mechanisms by which propofol produced its antinociceptive effect, we used specific antagonists for the cannabinoid CB1 (AM251) and CB2 (AM630) receptors and measured fatty-acid amide/endocannabinoid (anandamide, 2-arachidonylglycerol, and palmitoylethanolamide) concentrations in skin paw tissues. METHODS: Formalin tests were performed on 65 Wistar rats allocated to six different groups: 1) control (Intralipid™ 10%); 2) propofol (ED50 dose); 3) AM251; 4) AM251 + propofol; 5) AM630; 6) AM630 + propofol. Drugs were injected subcutaneously in the dorsal surface of the hind paw (50 μL) 15 min before 2.5% formalin injection into the same paw. Fatty-acid amide/endocannabinoid levels were measured by high performance liquid chromatography/mass spectrometry analysis. RESULTS: Propofol produced a dose-dependent antinociceptive effect for the early and late phases of the formalin test with an ED50 of 0.08 ± 0.061 μg for the latter phase. This effect was antagonized by AM251 and AM630. It was locally mediated, since a higher dose of propofol given in the contralateral paw was not antinociceptive. Finally, only paw concentrations of palmitoylethanolamide were significantly increased. CONCLUSION: In a test of inflammatory pain, locally injected propofol decreased pain behavior in a dose-dependent manner. This antinociceptive effect was mediated, in part, by CB1 and CB2 receptors. © 2007 by International Anesthesia Research Society.