Nieto M Mas, Guen S L E, Kieffer B L, Roques B P, Noble F
Neuropsychopharmacologie des Addictions, CNRS UMR 7157, Université René Descartes, Neuropsychopharmacologie des Addictions, 75270 Paris Cedex 06, France.
Neuroscience. 2005;135(2):305-13. doi: 10.1016/j.neuroscience.2005.06.025.
The endogenous pentapeptide enkephalins bind to the mu and delta opioid receptors, with a slightly higher affinity for the latter. It remains a controversy regarding the respective physiological role of mu and delta opioid receptors in the control of emotion and motivation. One of the difficulties to investigate this problem is the low tonic extracellular release of enkephalins in various brain structures. To overcome this problem the synaptic levels of these pentapeptides were enhanced by inhibition of enzymes involved in their catabolism with the selective inhibitor H3N-CH(CH2-CH2-S-CH3)-CH2-S-S-CH2-CH(CH2phi)-CONH-CH(CH2phi)-COOCH2phi (RB101). This compound was shown to increase the extracellular levels and lifetime of endogenous enkephalins. Similar responses were obtained in wild-type and mu opioid receptor knockout mice following RB 101 administration in behavioral tests measuring locomotor activity, anxiety (elevated O-maze), and motivation (forced swim test and conditioned suppression of motility). In contrast, RB 101 led to antinociceptive responses only in wild-type animals using hot plate and tail immersion tests. These results clearly demonstrate the critical role of delta opioid receptors activated by the endogenous opioid peptides, in the physiological control of emotion- and motivation-related behaviors. In contrast, antinociceptive modulation, at least with respect to thermal nociceptive stimuli, involves enkephalin-activated mu opioid receptors. These findings could open new perspectives in the treatment of mood disorders using either inhibitors of enkephalin catabolism or delta opioid agonists.
内源性五肽脑啡肽与μ和δ阿片受体结合，对后者的亲和力略高。关于μ和δ阿片受体在情绪和动机控制中的各自生理作用仍存在争议。研究这个问题的困难之一是脑啡肽在各种脑结构中的细胞外基础释放量较低。为了克服这个问题，通过用选择性抑制剂H3N-CH(CH2-CH2-S-CH3)-CH2-S-S-CH2-CH(CH2phi)-CONH-CH(CH2phi)-COOCH2phi（RB101）抑制参与其分解代谢的酶，提高了这些五肽的突触水平。该化合物被证明可增加内源性脑啡肽的细胞外水平和半衰期。在测量运动活性、焦虑（高架O迷宫）和动机（强迫游泳试验和运动条件抑制）的行为测试中，对野生型和μ阿片受体基因敲除小鼠给予RB 101后，得到了类似的反应。相比之下，仅在野生型动物中使用热板和尾浸试验时，RB 101才会产生抗伤害感受反应。这些结果清楚地证明了内源性阿片肽激活的δ阿片受体在与情绪和动机相关行为的生理控制中的关键作用。相比之下，至少就热伤害性刺激而言，抗伤害感受调节涉及脑啡肽激活的μ阿片受体。这些发现可能为使用脑啡肽分解代谢抑制剂或δ阿片激动剂治疗情绪障碍开辟新的前景。
