Guindon Josée, LoVerme Jesse, Piomelli Daniele, Beaulieu Pierre
Department of Pharmacology, Faculty of Medicine, Université de Montréal-CHUM, Montréal, Québec, Canada.
Anesth Analg. 2007 Jun;104(6):1563-9, table of contents. doi: 10.1213/01.ane.0000263278.05423.a3.
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 microg) 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.
Formalin tests were performed on 65 Wistar rats allocated to six different groups: 1) control (Intralipidtrade mark 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 microL) 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.
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 microg 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.
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.
丙泊酚可抑制脂肪酸酰胺水解酶，该酶负责花生四烯酸乙醇胺（一种内源性大麻素）的代谢。为研究丙泊酚的潜在镇痛作用，我们在动物后爪给予不同剂量（0.005、0.05、0.5、5和500微克）的该麻醉剂以确定半数有效剂量（ED50）。为进一步探究丙泊酚产生镇痛作用的机制，我们使用了大麻素CB1（AM251）和CB2（AM630）受体的特异性拮抗剂，并测量了后爪皮肤组织中脂肪酸酰胺/内源性大麻素（花生四烯酸乙醇胺、2-花生四烯酸甘油和棕榈酰乙醇胺）的浓度。
对65只Wistar大鼠进行福尔马林试验，将其分为六个不同组：1）对照组（10%的英脱利匹特商标）；2）丙泊酚组（ED50剂量）；3）AM251组；4）AM251 + 丙泊酚组；5）AM630组；6）AM630 + 丙泊酚组。在向同一只后爪注射2.5%福尔马林前15分钟，将药物（50微升）皮下注射到后爪背侧表面。通过高效液相色谱/质谱分析测量脂肪酸酰胺/内源性大麻素水平。
丙泊酚对福尔马林试验的早期和晚期阶段均产生剂量依赖性镇痛作用，后期的ED50为0.08±0.061微克。这种作用被AM251和AM630拮抗。它是局部介导的，因为在对侧后爪给予更高剂量的丙泊酚没有镇痛作用。最后，只有爪中棕榈酰乙醇胺的浓度显著增加。
在炎症性疼痛试验中，局部注射丙泊酚以剂量依赖性方式降低疼痛行为。这种镇痛作用部分由CB1和CB2受体介导。
