Adamson Barnes Nicholas S, Mitchell Vanessa A, Kazantzis Nicholas P, Vaughan Christopher W
Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, University of Sydney at Royal North Shore Hospital, NSW, Australia.
Br J Pharmacol. 2016 Jan;173(1):77-87. doi: 10.1111/bph.13337. Epub 2015 Dec 1.
While cannabinoids have been proposed as a potential treatment for neuropathic pain, they have limitations. Cannabinoid receptor agonists have good efficacy in animal models of neuropathic pain; they have a poor therapeutic window. Conversely, selective fatty acid amide hydrolase (FAAH) inhibitors that enhance the endocannabinoid system have a better therapeutic window, but lesser efficacy. We examined whether JZL195, a dual inhibitor of FAAH and monacylglycerol lipase (MAGL), could overcome these limitations.
C57BL/6 mice underwent the chronic constriction injury (CCI) model of neuropathic pain. Mechanical and cold allodynia, plus cannabinoid side effects, were assessed in response to systemic drug application.
JZL195 and the cannabinoid receptor agonist WIN55212 produced dose-dependent reductions in CCI-induced mechanical and cold allodynia, plus side effects including motor incoordination, catalepsy and sedation. JZL195 reduced allodynia with an ED50 at least four times less than that at which it produced side effects. By contrast, WIN55212 reduced allodynia and produce side effects with similar ED50s. The maximal anti-allodynic effect of JZL195 was greater than that produced by selective FAAH, or MAGL inhibitors. The JZL195-induced anti-allodynia was maintained during repeated treatment.
These findings suggest that JZL195 has greater anti-allodynic efficacy than selective FAAH, or MAGL inhibitors, plus a greater therapeutic window than a cannabinoid receptor agonist. Thus, dual FAAH/MAGL inhibition may have greater potential in alleviating neuropathic pain, compared with selective FAAH and MAGL inhibitors, or cannabinoid receptor agonists.
虽然大麻素已被提议作为治疗神经性疼痛的一种潜在疗法，但它们存在局限性。大麻素受体激动剂在神经性疼痛的动物模型中具有良好疗效；但其治疗窗较窄。相反，增强内源性大麻素系统的选择性脂肪酸酰胺水解酶（FAAH）抑制剂具有更好的治疗窗，但疗效较低。我们研究了FAAH和单酰甘油脂肪酶（MAGL）的双重抑制剂JZL195是否能克服这些局限性。
C57BL/6小鼠接受神经性疼痛的慢性缩窄损伤（CCI）模型。针对全身给药评估机械性和冷觉异常性疼痛以及大麻素副作用。
JZL195和大麻素受体激动剂WIN55212可使CCI诱导的机械性和冷觉异常性疼痛呈剂量依赖性降低，同时产生包括运动不协调、僵住症和镇静在内的副作用。JZL195减轻异常性疼痛的半数有效剂量（ED50）至少比其产生副作用时的剂量低四倍。相比之下，WIN55212减轻异常性疼痛和产生副作用的ED50相似。JZL195的最大抗异常性疼痛作用大于选择性FAAH或MAGL抑制剂所产生的作用。在重复治疗期间，JZL195诱导的抗异常性疼痛得以维持。
这些发现表明，JZL195比选择性FAAH或MAGL抑制剂具有更强的抗异常性疼痛疗效，且比大麻素受体激动剂具有更宽的治疗窗。因此，与选择性FAAH和MAGL抑制剂或大麻素受体激动剂相比，双重FAAH/MAGL抑制在减轻神经性疼痛方面可能具有更大潜力。
