Lomazzo Ermelinda, Bindila Laura, Remmers Floor, Lerner Raissa, Schwitter Claudia, Hoheisel Ulrich, Lutz Beat
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Department of Neurophysiology, CBTM, Medical Faculty Mannheim, Heidelberg University, Germany.
Neuropsychopharmacology. 2015 Jan;40(2):488-501. doi: 10.1038/npp.2014.198. Epub 2014 Aug 6.
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.
慢性应激、抑郁和焦虑的出现会增加人类的痛觉感受，并可能促使疼痛从局部疼痛转变为慢性广泛性疼痛。慢性广泛性疼痛的潜在机制仍然未知，这阻碍了有效药物治疗方法的开发。在此，我们将C57BL/6J小鼠暴露于慢性不可预测应激（CUS）中，以研究持续应激如何影响痛觉感受。接下来，给小鼠多次肌肉注射神经生长因子（NGF），这会诱发慢性广泛性痛觉过敏。因此，CUS和NGF的联合作用构成了一个心理生理损伤与持久痛觉过敏并存的模型。我们发现，CUS增加了小鼠的焦虑样和抑郁样行为，并增强了基础痛觉感受。当与重复注射NGF联合应用时，CUS引发了持续的、持久的广泛性痛觉过敏。为了评估一种治疗与应激相关的慢性疼痛的潜在治疗策略，我们假设内源性大麻素系统（ECS）可能是一个目标信号系统。我们发现，URB597（一种花生四烯乙醇胺降解酶脂肪酸酰胺水解酶（FAAH）的抑制剂）和JZL184（一种2-花生四烯酰甘油降解酶单酰甘油脂肪酶（MAGL）的抑制剂）可提高大脑和外周组织中的内源性大麻素（eCB）水平，并且二者均能有效减轻通过明暗试验测得的CUS诱导的焦虑以及CUS诱导的热痛觉过敏。值得注意的是，URB597可有效减轻CUS和NGF联合诱导的持久广泛性痛觉过敏，但JZL184则不能。同时抑制FAAH和MAGL并不能改善整体治疗效果。因此，我们的研究结果表明，用URB597增强花生四烯乙醇胺信号传导是一种有前景的药理学方法，可减轻应激暴露小鼠的慢性广泛性痛觉过敏，因此，它可能是治疗人类与神经精神疾病相关的慢性疼痛的一种潜在治疗策略。
