Cell
Volume 147, Issue 2, 14 October 2011, Pages 447-458
Journal home page for Cell

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

https://doi.org/10.1016/j.cell.2011.08.043Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► Unique isoforms of the μ-opioid receptor (MOR) separate itch from analgesia ► Heterodimers of MOR1D and gastrin-releasing peptide receptor (GRPR) form ► Molecular basis for opioid-induced itch relies on MOR1D activation of GRPR ► PLCβ3 and IP3R3 signal downstream of MOR1D-GRPR to trigger itch response

Cited by (0)

4

Present address: Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, TX 77030, USA

5

Present address: Haverford College, Haverford, PA 19041, USA

6

Present address: Department of Anesthesiology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin County 640, Taiwan (R.O.C.)

7

Present address: Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China