Noble F, Fournie-Zaluski M C, Roques B P
Department de Pharmacochimie Moléculaire et Structurale, INSERM U266, CNRS URA D 1500, Université René Descartes, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France.
Neuroscience. 1996 Dec;75(3):917-26. doi: 10.1016/0306-4522(96)00323-5.
Using the mouse caudate-putamen, where delta-opioid receptor subtypes have been shown to regulate adenylyl cyclase activity, we show in this study that endogenous enkephalins inhibit enzyme activity through activation of delta 1- and delta 2-opioid receptors. Thus, naltriben or 7-benzylidenenaltrexone as well as the delta-selective antagonist naltrindole (mixed delta 1 and delta 2 antagonist) antagonized inhibition of adenylyl cyclase activity induced by methionine- or leucine-enkephalin, while the micro-antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) was without effect. Furthermore, we have previously shown that activation of delta-opioid receptors increases cholecystokinin release in the central nervous system, resulting in a potentiation of micro-opioid antinociceptive responses, and the respective role of delta 1- and delta 2-opioid receptors in this facilitatory effect has now been evaluated. Activation of delta 2-opioid receptors, either by endogenous enkephalins protected from catabolism by the complete enkephalin-degrading enzyme inhibitor N-((R,S)-2-benzyl-3((S)(2-amino-4-methyl-thio) butyldithio)-1-oxopropyl)-L-phenyl-alanine benzyl ester (RB 101), or by the delta 2-selective agonist Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl) (BUBU), potentiated micro-opioid antinociceptive responses in the hot-plate test in mice. This effect was antagonized by a selective cholecystokinin-A antagonist. Activation of delta 1-opioid receptors by endogenous opioid peptides decreased the micro-opioid responses. These results suggest that stimulation of delta 2-opioid receptors potentiates micro-opioid analgesia in the hot-plate test in mice through an increase in endogenous cholecystokinin release, while activation of delta 1-opioid receptors could decrease it. Thus, the pre-existing physiological balance between opioid and cholecystokinin systems seems to be modulated in opposite directions depending on whether delta 1- or delta 2-opioid receptors are selectively activated. This is the first demonstration that endogenous enkephalins, methionine- and leucine-enkephalin, are the natural ligands of delta-opioid receptor subtypes, and that delta 2-opioid receptor activation may facilitate the endogenous cholecystokinin-related modulation of micro-opioid analgesia, while the delta 1-opioid receptors may have an inhibitory role. These results could have important applications for the characterization of opioid delta 1 and delta 2 as subtypes or subsites and in pain alleviation.
利用小鼠尾状核 - 壳核（已证明δ - 阿片受体亚型在此处调节腺苷酸环化酶活性），我们在本研究中表明，内源性脑啡肽通过激活δ1和δ2 - 阿片受体来抑制酶活性。因此，纳曲苄或7 - 亚苄基纳曲酮以及δ - 选择性拮抗剂纳曲吲哚（δ1和δ2混合型拮抗剂）可拮抗甲硫氨酸 - 或亮氨酸 - 脑啡肽诱导的腺苷酸环化酶活性抑制，而微拮抗剂D - Phe - Cys - Tyr - D - Trp - Orn - Thr - Pen - Thr - NH2（CTOP）则无此作用。此外，我们之前已表明，δ - 阿片受体的激活会增加中枢神经系统中胆囊收缩素的释放，从而增强微阿片类药物的抗伤害感受反应，现在已评估了δ1和δ2 - 阿片受体在这种促进作用中的各自作用。通过内源性脑啡肽（被完全脑啡肽降解酶抑制剂N - ((R,S) - 2 - 苄基 - 3((S)(2 - 氨基 - 4 - 甲基 - 硫代)丁基二硫代) - 1 - 氧代丙基) - L - 苯丙氨酸苄酯（RB 101）保护以免受分解代谢）或δ2 - 选择性激动剂Tyr - D - Ser(O - 叔丁基) - Gly - Phe - Leu - Thr(O - 叔丁基)（BUBU）激活δ2 - 阿片受体，可增强小鼠热板试验中的微阿片类药物抗伤害感受反应。这种作用被选择性胆囊收缩素 - A拮抗剂所拮抗。内源性阿片肽激活δ1 - 阿片受体可降低微阿片类药物反应。这些结果表明，在小鼠热板试验中，刺激δ2 - 阿片受体通过增加内源性胆囊收缩素释放来增强微阿片类药物镇痛作用，而激活δ1 - 阿片受体则可能降低该作用。因此，阿片系统和胆囊收缩素系统之间预先存在的生理平衡似乎会根据δ1或δ2 - 阿片受体是否被选择性激活而向相反方向调节。这是首次证明内源性脑啡肽、甲硫氨酸 - 和亮氨酸 - 脑啡肽是δ - 阿片受体亚型的天然配体，并且δ2 - 阿片受体激活可能促进内源性胆囊收缩素相关的微阿片类药物镇痛调节，而δ1 - 阿片受体可能具有抑制作用。这些结果对于将阿片δ1和δ2表征为亚型或亚位点以及在疼痛缓解方面可能具有重要应用。
