AMPK contributes to aerobic exercise-induced antinociception downstream of endocannabinoids
AMPK contributes to aerobic exercise-induced antinociception downstream of endocannabinoids
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DOI：
10.1016/j.neuropharm.2017.05.002
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发表时间：
2017-09-15
影响因子：
4.7
通讯作者：
Niederberger, Ellen
中科院分区：
文献类型：
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作者：
King-Himmelreich, Tanya S.;Moeser, Christine V.;Niederberger, Ellen
体育锻炼多次被认为与伤害性反应减少有关，但其潜在的机制仍未完全阐明。在这项研究中，我们研究了单次跑步机跑步对福尔马林炎性痛觉小鼠模型的运动诱导效应。作为潜在的分子介质，我们关注内源性内源性大麻素和AMP激活的蛋白激酶(AMPK)。我们的结果表明，野生型小鼠在跑步机运动后的福尔马林试验中伤害性反应降低，而运动对AMPKα2基因敲除小鼠的炎性伤害性反应没有影响。在野生型和AMPKα2基因敲除小鼠中，体力活动后内源性大麻素脱氧核糖核酸(AEA)水平均升高，同时AEA水解酶FAAH的表达降低，大麻素受体1(CB1)的水平升高。因此，在跑步机跑步之前用CB1反向激动剂AM251治疗野生型小鼠，可以逆转运动诱导的抗伤害感觉。然而，如果小鼠接受AM251和AMPK激活剂5-amino-1-beta-D-ribofuranosyl-imidazole-4-carboxamide(AICAR)的联合治疗，跑步机运动对炎性伤害性感受的积极作用得以恢复，这表明AMPK影响运动诱导的内源性大麻类化合物下游的抗伤害性感受。这一假设得到了细胞培养实验的进一步支持，该实验表明AMPK在AEA刺激神经细胞后被激活。综上所述，我们的数据表明AMPK在内源性大麻素介导的运动诱导的抗伤害感受中是一种中间效应。(C)2017爱思唯尔有限公司。保留所有权利。
Physical exercise has been repeatedly associated with decreased nociceptive responses but the underlying mechanisms have still not been fully clarified. In this study, we investigated exercise-induced effects after a single bout of treadmill running on the mouse model of formalin-induced inflammatory nociception. As potential molecular mediators, we focused on endogenous endocannabinoids as well as AMP-activated protein kinase (AMPK). Our results showed that wild type mice display a reduced nociceptive response in the formalin test after treadmill running, while exercise had no effect on inflammatory nociception in AMPK alpha 2 knockout mice. Levels of the endocannabinoid anandamide (AEA) were increased after physical activity in both wild type and AMPK alpha 2 knockout mice, in association with decreased expression of the AEA-hydrolyzing enzyme FAAH and an increased level of the cannabinoid receptor 1 (CB1). Accordingly, treatment of wild type mice with the CB1 inverse agonist AM251 prior to the treadmill running reversed exercise-induced antinociception. However, if mice received AM251 in combination with the AMPK activator 5-amino-1-beta-D-ribofuranosyl-imidazole-4-carboxamide (AICAR), the positive effect of treadmill running on inflammatory nociception was restored, indicating that AMPK affects exercise-induced antinociception downstream of endocannabinoids. This assumption was further supported by cell culture experiments showing AMPK activation after stimulation of neuronal cells with AEA.In conclusion, our data suggest that AMPK is an intermediate effector in endocannabinoid-mediated exercise-induced antinociception.This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". (C) 2017 Elsevier Ltd. All rights reserved.