Unidirectional Cross-Activation of GRPR by MOR1D Uncouples Itch and Analgesia Induced by Opioids

被引:231
作者
Liu, Xian-Yu [1 ,2 ,3 ,4 ]
Liu, Zhong-Chun [1 ,2 ,3 ,4 ]
Sun, Yan-Gang [1 ]
Ross, Michael [1 ]
Kim, Seungil [1 ,2 ,3 ,4 ]
Tsai, Feng-Fang [1 ]
Li, Qi-Fang [1 ,2 ,3 ,4 ]
Jeffry, Joseph [1 ,2 ,3 ,4 ]
Kim, Ji-Young [2 ,3 ,4 ]
Loh, Horace H. [5 ]
Chen, Zhou-Feng [1 ,2 ,3 ,4 ]
机构
[1] Washington Univ, Sch Med, Pain Ctr, Ctr Study Itch, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Pain Ctr, Dept Anesthesiol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Pain Ctr, Dept Psychiat, St Louis, MO 63110 USA
[4] Washington Univ, Sch Med, Pain Ctr, Dept Dev Biol, St Louis, MO 63110 USA
[5] Univ Minnesota, Dept Pharmacol, Minneapolis, MN 55455 USA
关键词
DORSAL-HORN NEURONS; MAMMALIAN BOMBESIN RECEPTORS; MORPHINE-INDUCED ANALGESIA; GASTROINTESTINAL TRANSIT; MOLECULAR-MECHANISMS; SPLICE VARIANTS; KNOCKOUT MICE; SPINAL-CORD; MU; PRURITUS;
D O I
10.1016/j.cell.2011.08.043
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Spinal opioid-induced itch, a prevalent side effect of pain management, has been proposed to result from pain inhibition. We now report that the m-opioid receptor (MOR) isoform MOR1D is essential for morphine-induced scratching (MIS), whereas the isoform MOR1 is required only for morphine-induced analgesia (MIA). MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, relaying itch information. We show that morphine triggers internalization of both GRPR and MOR1D, whereas GRP specifically triggers GRPR internalization and morphine-independent scratching. Providing potential insight into opioid-induced itch prevention, we demonstrate that molecular and pharmacologic inhibition of PLC beta 3 and IP3R3, downstream effectors of GRPR, specifically block MIS but not MIA. In addition, blocking MOR1D-GRPR association attenuates MIS but not MIA. Together, these data suggest that opioid-induced itch is an active process concomitant with but independent of opioid analgesia, occurring via the unidirectional cross-activation of GRPR signaling by MOR1D heterodimerization.
引用
收藏
页码:447 / 458
页数:12
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