title: Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids.
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.
authors: Center for the Study of Itch, Washington University School of Medicine Pain Center, St. Louis, MO 63110, USA.
authors: Xian-Yu
authors: XY
authors: Liu
authors: Zhong-Chun
authors: ZC
authors: Liu
authors: Yan-Gang
authors: YG
authors: Sun
authors: Michael
authors: M
authors: Ross
authors: Seungil
authors: S
authors: Kim
authors: Feng-Fang
authors: FF
authors: Tsai
authors: Qi-Fang
authors: QF
authors: Li
authors: Joseph
authors: J
authors: Jeffry
authors: Ji-Young
authors: JY
authors: Kim
authors: Horace H
authors: HH
authors: Loh
authors: Zhou-Feng
authors: ZF
authors: Chen
mesh_terms: D000595:Amino Acid Sequence; D000698:Analgesia; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009020:Morphine / Q000008:administration & dosage*; D010146:Pain / Q000188:drug therapy*; D011537:Pruritus / Q000139:chemically induced*; D018004:Receptors, Bombesin / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000701:Analgesics, Opioid; D018004:Receptors, Bombesin; D017450:Receptors, Opioid, mu; D009020:Morphine