Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain
Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain
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DOI：
10.1038/npp.2014.198
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发表时间：
2015-01-01
影响因子：
7.6
通讯作者：
Lutz, Beat
中科院分区：
文献类型：
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作者：
Lomazzo, Ermelinda;Bindila, Laura;Lutz, Beat
慢性应激、抑郁和焦虑的发生可以增加人类的伤害感受，并可能促进从局部疼痛向慢性广泛性疼痛的转变。慢性广泛性疼痛的潜在机制仍然未知，阻碍了有效药物治疗的发展。在这里，我们将C57 BL/6 J小鼠暴露于慢性不可预测的应激（CUS），以研究持续应激如何影响伤害性感受。接下来，小鼠接受多次肌内神经生长因子（NGF）注射，诱导慢性广泛伤害感受。因此，CUS和NGF的组合作为一个模型，其中心理生理损伤与持久的痛觉过敏共存。我们发现CUS增加了小鼠的焦虑和抑郁样行为，并增强了基础伤害感受。当与反复注射NGF共同应用时，CUS引起持续持久的广泛痛觉过敏。为了评估一种潜在的治疗策略，用于治疗慢性疼痛与压力，我们假设内源性大麻素系统（ECS）可能代表一个目标信号系统。我们发现，URB 597（一种花生四烯酸降解酶脂肪酸酰胺水解酶（FAAH）的抑制剂）和JZL 184（一种2-花生四烯酸甘油降解酶单酰基甘油脂肪酶（MAGL）的抑制剂）增加了大脑和外周的eCB水平，并且都能有效降低由光暗试验测量的焦虑和由热刺激引起的热痛觉过敏。值得注意的是，URB 597有效地减少了由CUS和NGF组合诱导的持久广泛的痛觉过敏，但JZL 184没有。同时抑制FAAH和MAGL并不能改善总体治疗反应。因此，我们的研究结果表明，用URB 597增强大麻素信号传导是一种很有前途的药理学方法，用于缓解应激小鼠的慢性广泛伤害感受，因此，它可能代表与人类神经精神疾病相关的慢性疼痛的潜在治疗策略。
The occurrence of chronic stress, depression, and anxiety can increase nociception in humans and may facilitate the transition from localized to chronic widespread pain. The mechanisms underlying chronic widespread pain are still unknown, hindering the development of effective pharmacological therapies. Here, we exposed C57BL/6J mice to chronic unpredictable stress (CUS) to investigate how persistent stress affects nociception. Next, mice were treated with multiple intramuscular nerve growth factor (NGF) injections, which induced chronic widespread nociception. Thus, combination of CUS and NGF served as a model where psychophysiological impairment coexists with long-lasting hyperalgesia. We found that CUS increased anxiety-and depression-like behavior and enhanced basal nociception in mice. When co-applied with repeated NGF injections, CUS elicited a sustained long-lasting widespread hyperalgesia. In order to evaluate a potential therapeutic strategy for the treatment of chronic pain associated with stress, we hypothesized that the endocannabinoid system (ECS) may represent a target signaling system. We found that URB597, an inhibitor of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), and JZL184, an inhibitor of the 2-arachidonoyl glycerol-degrading enzyme monoacylglycerol lipase (MAGL), increased eCB levels in the brain and periphery and were both effective in reducing CUS-induced anxiety measured by the light-dark test and CUS-induced thermal hyperalgesia. Remarkably, the long-lasting widespread hyperalgesia induced by combining CUS and NGF was effectively reduced by URB597, but not by JZL184. Simultaneous inhibition of FAAH and MAGL did not improve the overall therapeutic response. Therefore, our findings indicate that enhancement of anandamide signaling with URB597 is a promising pharmacological approach for the alleviation of chronic widespread nociception in stress-exposed mice, and thus, it could represent a potential treatment strategy for chronic pain associated with neuropsychiatric disorders in humans.