Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus.
Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus.
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DOI：
10.1016/j.neuropharm.2015.08.027
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发表时间：
2015-12
影响因子：
4.7
通讯作者：
Bohn LM
中科院分区：
文献类型：
--
作者：
Morgenweck J;Frankowski KJ;Prisinzano TE;Aubé J;Bohn LM
κ阿片受体（KOR）参与介导瘙痒;靶向该受体的激动剂已用于治疗慢性顽固性瘙痒。相反，拮抗剂在注射部位诱导英寸反应。作为G蛋白偶联受体（GPCR），KOR具有通过G蛋白和β抑制蛋白进行信号传导的潜力，然而，尚不清楚这些通路中的哪些参与KOR对瘙痒的调节。在这项研究中，通过使用β arrestin 2敲除（β arr 2-KO）小鼠以及最近描述的偏向性KOR激动剂（其使受体信号传导偏向G蛋白通路而非β arrestin 2募集），询问KOR在瘙痒中的作用是否涉及β arrestins。我们发现KOR拮抗剂nor-binaltorphimine（NorBNI）和5′-guanidinonaltrindole（5′GNTI）在C57 BL/6 J小鼠中诱导急性瘙痒，而在KOR-KO小鼠中的作用减弱。与野生型相比，β arr 2-KO小鼠对KOR拮抗剂诱导的瘙痒反应较少，但在磷酸氯喹（CP）诱导的瘙痒中未观察到基因型差异，表明拮抗剂可能利用KOR-β arrestin 2依赖性机制。KOR激动剂U 50，488 H在WT和β arr 2-KO小鼠中抑制CP诱导的瘙痒方面同样有效。此外，G蛋白偏向激动剂异喹啉酮2.1在抑制由KOR拮抗剂NorBNI或CP在C57 BL/6 J小鼠中诱导的瘙痒反应方面与U 50，488 H一样有效。总之，这些数据表明，KOR激动剂的抗炎症作用可能不需要β抑制蛋白。
The kappa opioid receptor (KOR) is involved in mediating pruritus; agonists targeting this receptor have been used to treat chronic intractable itch. Conversely, antagonists induce an inch response at the site of injection. As a G protein-coupled receptor (GPCR), the KOR has potential for signaling via G proteins and βarrestins, however, it is not clear which of these pathways are involved in the KOR modulation of itch. In this study asked whether the actions of KOR in pruritus involve βarrestins by using βarrestin2 knockout (βarr2-KO) mice as well as a recently described biased KOR agonist that biases receptor signaling toward G protein pathways over βarrestin2 recruitment. We find that the KOR antagonists nor-binaltorphimine (NorBNI) and 5′-guanidinonaltrindole (5′GNTI) induce acute pruritus in C57BL/6J mice, with reduced effects in KOR-KO mice. βarr2-KO mice display less of a response to KOR antagonist-induced itch compared to wild types, however no genotype differences are observed from chloroquine phosphate (CP)-induced itch, suggesting that the antagonists may utilize a KOR-βarrestin2 dependent mechanism. The KOR agonist U50,488H was equally effective in both WT and βarr2-KO mice in suppressing CP-induced itch. Furthermore, the G protein biased agonist, Isoquinolinone 2.1 was as effective as U50,488H in suppressing the itch response induced by KOR antagonist NorBNI or CP in C57BL/6J mice. Together these data suggest that the antipruritic effects of KOR agonists may not require βarrestins.