Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids

Xian Yu Liu, Zhong Chun Liu, Yan Gang Sun, Michael Ross, Seungil Kim, Feng Fang Tsai, Qi Fang Li, Joseph Jeffry, Ji Young Kim, Horace H. Loh, Zhou Feng Chen

Research output: Contribution to journalArticlepeer-review

206 Scopus citations

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.

Original languageEnglish
Pages (from-to)447-458
Number of pages12
JournalCell
Volume147
Issue number2
DOIs
StatePublished - Oct 14 2011

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