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Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids |
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| Authors: | Liu Xian-Yu Liu Zhong-Chun Sun Yan-Gang Ross Michael Kim Seungil Tsai Feng-Fang Li Qi-Fang Jeffry Joseph Kim Ji-Young Loh Horace H Chen Zhou-Feng |
| Affiliation: | 1 Center for the Study of Itch, Washington University School of Medicine Pain Center, St. Louis, MO 63110, USA 2 Departments of Anesthesiology, Psychiatry, and Developmental Biology, Washington University School of Medicine Pain Center, St. Louis, MO 63110, USA 3 Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA |
| Abstract: | Spinal opioid-induced itch, a prevalent side effect of pain management, has been proposed to result from pain inhibition. We now report that the μ-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 PLCβ3 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. |
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