Anderson Wayne B, Gould Michael J, Torres Romeo D, Mitchell Vanessa A, Vaughan Christopher W
Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
Neuropharmacology. 2014 Jun;81:224-30. doi: 10.1016/j.neuropharm.2013.12.018. Epub 2013 Dec 30.
The analgesic efficacy of cannabinoids in chronic pain models is limited by side-effects. It has been proposed that this might be overcome by using agents which indirectly activate the endocannabinoid system. We examined the analgesic and side-effect profile of the dual FAAH/MAGL inhibitor JZL195 in an inflammatory pain model. The effect of systemic injections of a range of doses of JZL195 and the pan-cannabinoid receptor agonist WIN55212 were performed 1 day following intraplantar injection of CFA in C57BL/6 mice. JZL195 and WIN55212 both reduced mechanical allodynia and thermal hyperalgesia, and produced catalepsy and sedation in a dose dependent manner. Unlike WIN55212, JZL195 reduced allodynia at doses below those at which side-effects were observed. The effects of JZL195 and WIN55212 were abolished by co-application with the CB1 antagonist AM251. The CB2 antagonist also reduced the JZL195 anti-allodynia, and reversed the WIN55212 anti-allodynia. The reduction in allodynia produced by JZL195 was greater than that produced individually by the FAAH and MAGL inhibitors, URB597 and JZL184. These findings suggest that JZL195 reduces inflammation induced allodynia at doses below those which produce side-effects, and displays greater efficacy that FAAH or MAGL inhibitors. Thus, dual FAAH/MAGL inhibition has the potential to alleviate inflammatory pain with reduced cannabinoid-like side-effects.
大麻素在慢性疼痛模型中的镇痛效果受到副作用的限制。有人提出，使用间接激活内源性大麻素系统的药物可能会克服这一问题。我们在炎症性疼痛模型中研究了双重脂肪酸酰胺水解酶（FAAH）/单酰甘油脂肪酶（MAGL）抑制剂JZL195的镇痛和副作用情况。在C57BL/6小鼠足底注射弗氏完全佐剂（CFA）1天后，进行了一系列剂量的JZL195全身注射以及泛大麻素受体激动剂WIN55212的效果研究。JZL195和WIN55212均能减轻机械性异常性疼痛和热痛觉过敏，并以剂量依赖性方式产生僵住症和镇静作用。与WIN55212不同，JZL195在低于观察到副作用的剂量下就能减轻异常性疼痛。JZL195和WIN55212的作用在与CB1拮抗剂AM251共同应用时被消除。CB2拮抗剂也降低了JZL195的抗异常性疼痛作用，并逆转了WIN55212的抗异常性疼痛作用。JZL195产生的异常性疼痛减轻程度大于FAAH和MAGL抑制剂URB597和JZL184单独产生的减轻程度。这些发现表明，JZL195在低于产生副作用的剂量下就能减轻炎症诱导的异常性疼痛，并且显示出比FAAH或MAGL抑制剂更高的疗效。因此，双重FAAH/MAGL抑制有潜力在减轻类大麻素样副作用的情况下缓解炎症性疼痛。
