Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants
Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants
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DOI：
10.1002/syn.21914
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发表时间：
2016-10-01
期刊：
影响因子：
2.3
通讯作者：
Pasternak, Gavril W.
中科院分区：
文献类型：
--
作者：
Grinnell, Steven G.;Ansonoff, Michael;Pasternak, Gavril W.
丁丙诺啡长期以来被归类为mu镇痛药，尽管其对其他阿片受体类和孤儿蛋白FQ/伤害肽ORL1受体的高亲和力可能有助于其其他作用。目前的研究证实了丁丙诺啡镇痛的mu机制，涉及mu受体剪接变异的几个亚群。丁丙诺啡镇痛依赖于外显子1相关的传统全长7跨膜（7TM）和外显子11相关的截断6跨膜（6TM）莫尔-1变异的表达。在遗传模型中，delta， kappa1或ORL1受体的破坏对丁丙诺啡镇痛没有影响，而在1外显子敲除（KO）小鼠中丢失传统的7TM or -1变异显著降低丁丙诺啡镇痛。在外显子11号KO小鼠中缺失的6TM突变完全消除了丁丙诺啡镇痛作用。与镇痛不同的是，胃肠道转运的抑制和运动活动的刺激与截断的6TM变体无关。在仍然表达7TM变体的11外显子KO小鼠中，用慢病毒恢复6TM变体的表达挽救了丁丙诺啡镇痛。尽管在表达DOR-1的CHO细胞中，丁丙诺啡能有效刺激S-35- gtp γ S结合，但在高达10 μ m的剂量下，丁丙诺啡无法激活β -arrestin-2结合。丁丙诺啡在表达DOR-1的细胞中是拮抗剂，在KOR-1细胞中是逆激动剂。丁丙诺啡镇痛是复杂的，需要多个受体剪接变异类，但其他作用可能涉及其他受体。
Buprenorphine has long been classified as a mu analgesic, although its high affinity for other opioid receptor classes and the orphanin FQ/nociceptin ORL1 receptor may contribute to its other actions. The current studies confirmed a mu mechanism for buprenorphine analgesia, implicating several subsets of mu receptor splice variants. Buprenorphine analgesia depended on the expression of both exon 1-associated traditional full length 7 transmembrane (7TM) and exon 11-associated truncated 6 transmembrane (6TM) MOR-1 variants. In genetic models, disruption of delta, kappa1 or ORL1 receptors had no impact on buprenorphine analgesia, while loss of the traditional 7TM MOR-1 variants in an exon 1 knockout (KO) mouse markedly lowered buprenorphine analgesia. Loss of the truncated 6TM variants in an exon 11 KO mouse totally eliminated buprenorphine analgesia. In distinction to analgesia, the inhibition of gastrointestinal transit and stimulation of locomotor activity were independent of truncated 6TM variants. Restoring expression of a 6TM variant with a lentivirus rescued buprenorphine analgesia in an exon 11 KO mouse that still expressed the 7TM variants. Despite a potent and robust stimulation of S-35-GTP gamma S binding in MOR-1 expressing CHO cells, buprenorphine failed to recruit beta-arrestin-2 binding at doses as high as 10 mu M. Buprenorphine was an antagonist in DOR-1 expressing cells and an inverse agonist in KOR-1 cells. Buprenorphine analgesia is complex and requires multiple mu receptor splice variant classes but other actions may involve alternative receptors.