A comparison of noninternalizing (Herkinorin) and internalizing (DAMGO) μ-opioid agonists on cellular markers related to opioid tolerance and dependence
A comparison of noninternalizing (Herkinorin) and internalizing (DAMGO) μ-opioid agonists on cellular markers related to opioid tolerance and dependence
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DOI：
10.1002/syn.20356
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发表时间：
2007-03-01
期刊：
影响因子：
2.3
通讯作者：
Rothman, Richard B.
中科院分区：
文献类型：
--
作者：
Xu, Heng;Partilla, John S.;Rothman, Richard B.
先前的研究表明 Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) 和(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(苯甲酰氧基)-2-(3-呋喃基)十二氢-6a,10b-二甲基-4,10-二氧代-2H-萘并-[2,1-c]吡喃-7-甲酸甲酯（海葵林）是完全有效的μ激动剂。 Herkinorin (HERK) 与 DAMGO 不同，即使在过度表达 β-arrestin 的细胞中，也不会招募 β-arrestin 并促进 mu-受体内化。我们假设长期 HERK 和 DAMGO 治疗会对耐受和依赖性的细胞标志物产生不同的影响。将表达克隆的人μ受体的CHO细胞用10μM DAMGO、HERK、吗啡或培养基处理20小时。 DAMGO 和 HERK 在 [S-35]-GTP-gamma-S 结合测定中均充当完全激动剂，E-MAX 值为 230%，EC50 值分别为 12.8 和 92.5 nM。在 cAMP 测定中，DAMGO 和 HERK 具有相似的 EMAX 值（接近 80%）和 EC50 值，分别为 3.23 和 48.7 nM。在 [S-35]GTP-gamma-S 结合测定中，长期接触这两种药物会对这两种药物产生中等耐受性（类似于 2 至 5 倍）。在 cAMP 测定中，慢性 DAMGO 对两种药物产生耐受性（大约 3 至 4 倍）。慢性 HERK 消除了这两种药物抑制毛喉素刺激的 cAMP 积累的能力。慢性 DAMGO 增加，慢性 HERK 减少，毛喉素刺激 cAMP 积累。纳洛酮在慢性 HERK（但不是 DAMGO）后诱导毛喉素刺激的 cAMP 积累大量增加。结合已发表的数据来看，当前数据表明内化和非内化 mu 激动剂都会产生耐受和依赖性的细胞迹象。
Previous studies established that Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) and (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(Benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester (herkinorin) are fully efficacious mu-agonists. Herkinorin (HERK), unlike DAMGO, does not recruit beta-arrestin and promote mu-receptor internalization, even in cells that over express beta-arrestin. We hypothesized that chronic HERK and DAMGO treatment will differentially affect cellular markers of tolerance and dependence. CHO cells expressing the cloned human mu-receptor were treated for 20 h with 10 mu M DAMGO, HERK, morphine, or medium. Both DAMGO and HERK acted as full agonists in the [S-35]-GTP-gamma-S binding assay with E-MAX values of 230% and EC50 values of 12.8 and 92.5 nM, respectively. In the cAMP assay, DAMGO and HERK had similar EMAX values of similar to 80% and EC50 values of 3.23 and 48.7 nM, respectively. Chronic exposure to both drugs produced moderate tolerance to both drugs (similar to 2 to 5 fold) in the [S-35]GTP-gamma-S binding assay. In the cAMP assay, chronic DAMGO produced tolerance to both drugs (similar to 3 to 4 fold). Chronic HERK eliminated the ability of either drug to inhibit forskolin-stimulated cAMP accumulation. Chronic DAMGO increased, and chronic HERK decreased, forskolin-stimulated cAMP accumulation. Naloxone, after chronic HERK (but not DAMGO) induced a large increase in forskolin-stimulated cAMP accumulation. Viewed collectively with published data, the current data indicate that both internalizing and noninternalizing mu-agonists produce cellular signs of tolerance and dependence.