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

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

doi:10.1016/j.cell.2011.08.043

Cited by 247 publications

(268 citation statements)

References 68 publications

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“…A recent study demonstrated that GRPR can heteromerize with an isoform of the μ-opioid receptor MOR1D (44). This interaction explains the usual itch that accompanies morphine treatments, which could now be inhibited by preventing the interaction between the two GPCRs.…”

Section: Discussionmentioning

confidence: 99%

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

Czepielewski

Porto

Rizzo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Neutrophil migration to inflamed sites is crucial for both the initiation of inflammation and resolution of infection, yet these cells are involved in perpetuation of different chronic inflammatory diseases. Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors (GPCRs) involved in signal transmission in both central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. RC-3095 is a selective GRPR antagonist, recently found to have antiinflammatory properties in arthritis and sepsis models. Here we demonstrate that i.p. injection of GRP attracts neutrophils in 4 h, and attraction is blocked by RC-3095. Macrophage depletion or neutralization of TNF abrogates GRP-induced neutrophil recruitment to the peritoneum. In vitro, GRP-induced neutrophil migration was dependent on PLC-β2, PI3K, ERK, p38 and independent of Gαi protein, and neutrophil migration toward synovial fluid of arthritis patients was inhibited by treatment with RC-3095. We propose that GRPR is an alternative chemotactic receptor that may play a role in the pathogenesis of inflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

Czepielewski

Porto

Rizzo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The existence of an itch-specific pathway was supported by the identification of histamine-selective C fibers in human skin (9), and by the report that gastrin-releasing peptide (GRP) is an itch-selective transmitter of DRG neurons (10) that activates the GRP receptor (GRPR) on spinal neurons, which transmit itch but not pain (11). A heterodimer of the GRPR and a μ-opioid receptor (MOR) variant, MOR1D, in spinal neurons may mediate opioid-induced itch (12). However, sensory nerves in the skin are selective but not specific for histamine, since they also respond to nociceptive stimuli such as capsaicin (13), an agonist of the transient receptor potential vanilloid 1 channel (TRPV1), and DRG nociceptors expressing TRPV1 are necessary for scratching behavior (14).…”

Section: Introductionmentioning

confidence: 90%

The TGR5 receptor mediates bile acid–induced itch and analgesia

et al. 2013

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Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucineenkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide-and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.

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“…In the spinal cord, the opioid μ-receptor isoform MoR1d heterodimerizes with the bombesin BB 2 receptor, and the stimulation of MoR1d by morphine produces an effect similar to the stimulation of the BB 2 receptor. 102) Analgesia induced by intracisternal injection of morphine is antagonized by naloxonazine, an opioid μ 1 -receptor antagonist, but scratching induced by intracisternal morphine is not inhibited by naloxonazine.…”

Section: Itch-inhibitory Systemmentioning

confidence: 99%

Potential New Therapeutic Targets for Pathological Pruritus

Kuraishi

2013

Biological & Pharmaceutical Bulletin

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Very few approved medications are indicated for the treatment of pruritus, and drug development for pruritic diseases is awaited. During the past two decades, progress has been made in understanding the molecular basis of the physiology and pathophysiology of pruritus. Newly identified potential targets for pathological pruritus include receptors (histamine H 4 receptor, leukotriene B 4 receptors, interleukin-31 receptor A, bombesin BB 2 receptor, toll-like receptor 3, α-adrenoceptor, and opioid μ-and κ-receptors), channels (transient receptor potential (TRP) V3 and TRPA1 channels), and enzymes (histidine decarboxylase, sphingomyelin glucosylceramide deacylase, 5-lipoxygenase, leukotriene A 4 hydrolase, and autotaxin). The development of specific, effective blockers and agonists/antagonists of these targets is awaited.

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

Cited by 247 publications

References 68 publications

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

The TGR5 receptor mediates bile acid–induced itch and analgesia

Potential New Therapeutic Targets for Pathological Pruritus

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