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 language | English (US) |
|---|---|
| Pages (from-to) | 447-458 |
| Number of pages | 12 |
| Journal | Cell |
| Volume | 147 |
| Issue number | 2 |
| DOIs | |
| State | Published - Oct 14 2011 |
Bibliographical note
Funding Information:We thank J. Yin, S. Weng, Y.C. Pan, and Z.Q. Zhao for technical help and comments, C.J. Coscia, Y.X. Pan, and G.W. Pasternak for MOR1 and MOR1D plasmids, E. Wada and J. Battey for GRPR antibodies, P. Sternweis for PLCβ3 antibody, E. Liman for IP3R3 antibody, D. Coy for a GRPR antagonist, B.W. Li for qRT-PCR help, and W. Huh for LCM. We also thank M. Bruchas for comments. J.J. has been supported by a NIDA training grant. The work was supported by a NIAMS grant to Z.-F.C.
