Bailey Christopher P, Couch Daniel, Johnson Elizabeth, Griffiths Katie, Kelly Eamonn, Henderson Graeme
Department of Pharmacology, University of Bristol, School of Medical Sciences, Bristol BS8 1TD, United Kingdom.
J Neurosci. 2003 Nov 19;23(33):10515-20. doi: 10.1523/JNEUROSCI.23-33-10515.2003.
Mu-opioid receptors (MORs) exhibit rapid desensitization and internalization during exposure to various opioid agonists. In some studies, however, morphine has been observed to produce little MOR desensitization or internalization. We examined desensitization in mature rat locus ceruleus (LC) neurons and confirmed that morphine is a very poor desensitizing agent, whereas [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO), a high-efficacy agonist, and methadone, an agonist we observed to be of equivalent efficacy to morphine, produced profound rapid desensitization. Similarly, by measuring plasma membrane receptor levels in HEK293 cells stably expressing T7-epitope-tagged rat MOR1 at near physiological levels (HEK293-MOR1 cells), DAMGO and methadone but not morphine caused rapid MOR internalization. It has been reported that a low concentration of DAMGO, coapplied with morphine, caused morphine to induce MOR internalization. We examined whether this interaction occurred in mature mammalian neurons at the level of receptor desensitization. Coapplication of low concentrations of DAMGO did not increase morphine-induced desensitization in LC neurons but caused a lesser degree of desensitization than DAMGO alone. We also failed to observe an enhancement by DAMGO of morphine-induced desensitization in the electrically stimulated guinea pig ileum myenteric plexus-longitudinal muscle preparation. In HEK293-MOR1 cells, low concentrations of DAMGO did not convert morphine into a receptor-internalizing agent. The data presented here fail to support the theory that low concentrations of DAMGO can increase morphine-induced MOR desensitization or internalization.
μ-阿片受体（MORs）在暴露于各种阿片类激动剂时会表现出快速脱敏和内化。然而，在一些研究中，已观察到吗啡几乎不会引起MOR脱敏或内化。我们检测了成年大鼠蓝斑（LC）神经元中的脱敏情况，并证实吗啡是一种非常弱的脱敏剂，而高效激动剂[D-丙氨酸2，N-甲基苯丙氨酸4，甘醇5]脑啡肽（DAMGO）和我们观察到与吗啡效力相当的激动剂美沙酮，则会产生显著的快速脱敏。同样，通过测量稳定表达接近生理水平的T7表位标签大鼠MOR1的HEK293细胞（HEK293-MOR1细胞）中的质膜受体水平，DAMGO和美沙酮而非吗啡会导致MOR快速内化。据报道，低浓度的DAMGO与吗啡共同应用时，会使吗啡诱导MOR内化。我们研究了这种相互作用是否在成熟哺乳动物神经元的受体脱敏水平上发生。低浓度DAMGO与吗啡共同应用时，并不会增加LC神经元中吗啡诱导的脱敏，但与单独使用DAMGO相比，脱敏程度较低。在电刺激的豚鼠回肠肌间神经丛-纵肌制备中，我们也未观察到DAMGO增强吗啡诱导的脱敏。在HEK293-MOR1细胞中，低浓度的DAMGO不会使吗啡转变为受体内化剂。此处呈现的数据不支持低浓度DAMGO可增加吗啡诱导的MOR脱敏或内化这一理论。
