Coexpression of δ- and μ-opioid receptors in nociceptive sensory neurons

Wang, Haibo; Zhao, Bo; Zhong, Yan-Qing; Li, Kaicheng; Li, Ziyan; Wang, Qiong; Lu, Yin-Jing; Zhang, Zhenning; He, Shaoqiu; Zheng, Han-Cheng; Wu, Shengxi; Hökfelt, Tomas; Liu, Bao; Zhang, Xu

doi:10.1073/pnas.1008382107

Cited by 192 publications

(227 citation statements)

References 45 publications

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“…However the concentration of DAMGO used was high, potentially resulting in saturation of downstream second messenger pathways / effecter ion channels which may have prevented further inhibition. Despite their well-documented analgesic effects much remains to be understood regarding opioid receptor physiology in colonic extrinsic sensory afferents, with the potential for heteromeric complexes of opioid receptors to activate multiple G-protein receptor signaling pathways and potentially act on numerous effecter ion channels (Costantino et al, 2012;Wang et al, 2010). Further, mice lacking MOR have been shown to be more susceptible to TNBS induced colonic inflammation, indicating MOR activation may also have prominent effects on the immune system (Philippe et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

Hughes

Moretta

Lim

et al. 2014

Brain, Behavior, and Immunity

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Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients, Brain, Behavior, and Immunity (2014), doi: http://dx.doi.org/10. 1016/j.bbi.2014.07.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. supernatants from HS and IBS patients were applied to colo-rectal sensory afferent endings in mice with post-inflammatory chronic visceral hypersensitivity (CVH). β-endorphin was identified predominantly in monocyte / macrophages relative to T or B cells in human PBMC and colonic lamina propria. Monocyte derived β-endorphin levels and colonic macrophage numbers were lower in IBS patients than healthy subjects. PBMC supernatants from healthy subjects had greater inhibitory effects on colo-rectal afferent mechanosensitivity than those from IBS patients. The inhibitory effects of PBMC supernatants were more prominent in CVH mice compared to healthy mice due to an increase in µ-opioid receptor expression in dorsal root ganglia neurons in CVH mice. Monocyte / macrophages are the predominant immune cell type responsible for β-endorphin secretion in humans. IBS patients have lower monocyte derived β-endorphin levels than healthy subjects, causing less inhibition of colonic afferent endings. Consequently, altered immune function contributes toward visceral hypersensitivity in IBS.

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Section: Discussionmentioning

confidence: 99%

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

Hughes

Moretta

Lim

et al. 2014

Brain, Behavior, and Immunity

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“…16,17 The rightward shift in the SNC80 dose−response curve in both μ-KO and δ-KO mice demonstrates that both μ-and δ-opioid receptor protomers in the heteromeric complex contribute to the antinociceptive activity of SNC80 in wild-type mice. This result is consistent with prior studies showing that SNC80-induced antinociception possesses both δ-and μ-opioid receptor-mediated 21,22 components.…”

mentioning

confidence: 95%

“…15 Additionally, in vitro studies on the effects of SNC80 on opioid receptors suggested the involvement of μ-opioid receptors on the activity of SNC80. These included the finding that colocalized μ-and δ-opioid receptors in large and small dorsal root ganglion (DRG) neurons 16 are cointernalized into the same subcellular compartment for lysosomal degradation upon treatment with SNC80. 17 These reports point to the involvement of both μ-and δ-opioid receptors in the activity of SNC80.…”

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confidence: 99%

The δ Opioid Receptor Agonist SNC80 Selectively Activates Heteromeric μ–δ Opioid Receptors

Metcalf

Yekkirala

Powers

et al. 2012

ACS Chem. Neurosci.

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Coexpressed and colocalized μ-and δ-opioid receptors have been established to exist as heteromers in cultured cells and in vivo. However the biological significance of opioid receptor heteromer activation is less clear. To explore this significance, the efficacy of selective activation of opioid receptors by SNC80 was assessed in vitro in cells singly and coexpressing opioid receptors using a chimeric G-proteinmediated calcium fluorescence assay, SNC80 produced a substantially more robust response in cells expressing μ−δ heteromers than in all other cell lines. Intrathecal SNC80 administration in μ-and δ-opioid receptor knockout mice produced diminished antinociceptive activity compared with wild type. The combined in vivo and in vitro results suggest that SNC80 selectively activates μ−δ heteromers to produce maximal antinociception. These data contrast with the current view that SNC80 selectively activates δ-opioid receptor homomers to produce antinociception. Thus, the data suggest that heteromeric μ−δ receptors should be considered as a target when SNC80 is employed as a pharmacological tool in vivo. KEYWORDS: μ opioid receptor, δ opioid receptor, μ−δ heteromer, SNC80, knockout, antinociception C ompound SNC80 (Figure 1) has been employed as the prototypic nonpeptide, selective δ-opioid receptor agonist for nearly 20 years. The experimental techniques employed to define the δ-selectivity of SNC80 included radioligand binding, smooth muscle assays, and in vivo antagonism studies employing selective δ-antagonists. 1−4 SNC80 has found broad recognition and adoption as a selective δ-agonist standard, occupying the previously vacant nonpeptide selective δ-agonist niche in the opioid pharmacological toolbox. 3 However, in view of the discovery of opioid receptor heteromers as targets for ligands over the past decade, it is possible that opioid receptor heteromers may be activated by SNC80. In this regard, three heteromers, μ−δ, 5 μ−κ, 6 and κ−δ, 7 have been established in heterologous cell lines, 8 and selective ligands that target these heteromers have been identified for each of the above heteromers. 9−11 Moreover, heteromeric μ−δ receptors have been detected using selective antibodies in both cultured cells and DRG neurons. 12 Thus, δ-receptors organized as heteromers could be relevant in the action of SNC80.In this regard, SNC80-treated μ-opioid receptor knockout (μ-KO) mice have been found to be without effect in a visceral antiwrithing test. 13 Also, SNC80 produced an antihyperalgesic effect in WT mice but lacked this effect in μ-KO mice, 14 an effect similar to a separate study in δ-KO mice. 15 Additionally, in vitro studies on the effects of SNC80 on opioid receptors suggested the involvement of μ-opioid receptors on the activity of SNC80. These included the finding that colocalized μ-and δ-opioid receptors in large and small dorsal root ganglion (DRG) neurons 16 are cointernalized into the same subcellular compartment for lysosomal degradation upon treatment with

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“…Double immunofluorescence staining showed that DORs were present in SP-and CGRP-positive LDCVs in small DRG neurons in mice ( Figure 2A and Supplementary information, Figure S2A). This immunostaining pattern, which was shown with antibodies against DOR1 [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] , was abolished by the deletion of Oprd1 exon 1 in mice (Supplementary information, Figure S2A). Furthermore, β2 AR, G αi2 , PLCβ2, VGCC α2δ1 and P2X purinoceptor 2 (P2X 2 ) were present in SP-positive LDCVs in small DRG neurons (Figure 2A).…”

Section: Ldcv Localization Of Gpcrs Signaling Molecules and Ion Chanmentioning

confidence: 99%

Transport of receptors, receptor signaling complexes and ion channels via neuropeptide-secretory vesicles

Zhao

Wang

et al. 2011

Cell Res

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Stimulus-induced exocytosis of large dense-core vesicles (LDCVs) leads to discharge of neuropeptides and fusion of LDCV membranes with the plasma membrane. However, the contribution of LDCVs to the properties of the neuronal membrane remains largely unclear. The present study found that LDCVs were associated with multiple receptors, channels and signaling molecules, suggesting that neuronal sensitivity is modulated by an LDCV-mediated mechanism. Liquid chromatography-mass spectrometry combined with immunoblotting of subcellular fractions identified 298 proteins in LDCV membranes purified from the dorsal spinal cord, including G-protein-coupled receptors, G-proteins and other signaling molecules, ion channels and trafficking-related proteins. Morphological assays showed that δ-opioid receptor 1 (DOR1), β2 adrenergic receptor (AR), G αi2 , voltage-gated calcium channel α2δ1 subunit and P2X purinoceptor 2 were localized in substance P (SP)-positive LDCVs in small-diameter dorsal root ganglion neurons, whereas β1 AR, Wnt receptor frizzled 8 and dishevelled 1 were present in SP-negative LDCVs. Furthermore, DOR1/G αi2 /G β1γ5 /phospholipase C β2 complexes were associated with LDCVs. Blockade of the DOR1/ G αi2 interaction largely abolished the LDCV localization of G αi2 and impaired stimulation-induced surface expression of G αi2 . Thus, LDCVs serve as carriers of receptors, ion channels and preassembled receptor signaling complexes, enabling a rapid, activity-dependent modulation of neuronal sensitivity.

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Coexpression of δ- and μ-opioid receptors in nociceptive sensory neurons

Cited by 192 publications

References 45 publications

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

The δ Opioid Receptor Agonist SNC80 Selectively Activates Heteromeric μ–δ Opioid Receptors

Transport of receptors, receptor signaling complexes and ion channels via neuropeptide-secretory vesicles

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