Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine neuropathic pain model
Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine neuropathic pain model
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DOI：
10.1111/bph.13337
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发表时间：
2016-01-01
影响因子：
7.3
通讯作者：
Vaughan, Christopher W.
中科院分区：
文献类型：
--
作者：
Barnes, Nicholas S. Adamson;Mitchell, Vanessa A.;Vaughan, Christopher W.
背景和目的虽然大麻素已被提议作为神经性疼痛的潜在治疗方法，但它们有局限性。大麻素受体激动剂在神经病理性疼痛动物模型中具有良好疗效；他们的治疗窗口很差。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，但疗效较差。我们检查了 FAAH 和单酰甘油脂肪酶 (MAGL) 的双重抑制剂 JZL195 是否可以克服这些限制。实验方法 C57BL/6 小鼠经历了神经性疼痛的慢性压迫性损伤 (CCI) 模型。评估全身药物应用对机械性和冷异常性疼痛以及大麻素副作用的影响。关键结果 JZL195 和大麻素受体激动剂 WIN55212 可以剂量依赖性地减少 CCI 引起的机械性和冷性异常性疼痛，以及包括运动不协调、僵住和镇静在内的副作用。 JZL195 可减少异常性疼痛，其 ED50 至少比其产生副作用时低四倍。相比之下，WIN55212 减少了异常性疼痛并产生了与 ED50 类似的副作用。 JZL195 的最大抗异常性疼痛效果大于选择性 FAAH 或 MAGL 抑制剂产生的效果。在重复治疗过程中，JZL195 诱导的抗异常性疼痛得以维持。结论和意义这些研究结果表明，JZL195 比选择性 FAAH 或 MAGL 抑制剂具有更大的抗异常性疼痛功效，并且比大麻素受体激动剂具有更大的治疗窗。因此，与选择性 FAAH 和 MAGL 抑制剂或大麻素受体激动剂相比，FAAH/MAGL 双重抑制可能在减轻神经性疼痛方面具有更大的潜力。
Background and PurposeWhile 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.Experimental ApproachC57BL/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.Key ResultsJZL195 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.Conclusions and ImplicationsThese 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.