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Facilitation of μ-Opioid Receptor Activity by Preventing δ-Opioid Receptor-Mediated Codegradation

δ-opioid receptors (DORs) form heteromers with μ-opioid receptors (MORs) and negatively regulate MOR-mediated spinal analgesia. However, the underlying mechanism remains largely unclear. The present study shows that the activity of MORs can be enhanced by preventing MORs from DOR-mediated codegradat... Full description

Journal Title: Neuron 2011, Vol.69(1), pp.120-131
Main Author: He, Shao-Qiu
Other Authors: Zhang, Zhen-Ning , Guan, Ji-Song , Liu, Hong-Rui , Zhao, Bo , Wang, Hai-Bo , Li, Qian , Yang, Hong , Luo, Jie , Li, Zi-Yan , Wang, Qiong , Lu, Ying-Jin , Bao, Lan , Zhang, Xu
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0896-6273 ; DOI: 10.1016/j.neuron.2010.12.001
Link: http://dx.doi.org/10.1016/j.neuron.2010.12.001
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recordid: sciversesciencedirect_elsevierS0896-6273(10)00986-4
title: Facilitation of μ-Opioid Receptor Activity by Preventing δ-Opioid Receptor-Mediated Codegradation
format: Article
creator:
  • He, Shao-Qiu
  • Zhang, Zhen-Ning
  • Guan, Ji-Song
  • Liu, Hong-Rui
  • Zhao, Bo
  • Wang, Hai-Bo
  • Li, Qian
  • Yang, Hong
  • Luo, Jie
  • Li, Zi-Yan
  • Wang, Qiong
  • Lu, Ying-Jin
  • Bao, Lan
  • Zhang, Xu
subjects:
  • Morphine
  • Opioid Receptors (Type Delta)
  • Spinal Cord
  • Pain Perception
  • Drug Tolerance
  • Transmembrane Domains
  • Endocytosis
  • Ubiquitination
  • Analgesia
  • Cell Membranes
  • Opioid Receptors (Type Mu)
  • Opioids
  • Analgesics
  • Fusion Protein
  • Lysosomes
  • Neurobiology
ispartof: Neuron, 2011, Vol.69(1), pp.120-131
description: δ-opioid receptors (DORs) form heteromers with μ-opioid receptors (MORs) and negatively regulate MOR-mediated spinal analgesia. However, the underlying mechanism remains largely unclear. The present study shows that the activity of MORs can be enhanced by preventing MORs from DOR-mediated codegradation. Treatment with DOR-specific agonists led to endocytosis of both DORs and MORs. These receptors were further processed for ubiquitination and lysosomal degradation, resulting in a reduction of surface MORs. Such effects were attenuated by treatment with an interfering peptide containing the first transmembrane domain of MOR (MOR TM1), which interacted with DORs and disrupted the MOR/DOR interaction. Furthermore, the systemically applied fusion protein consisting of MOR TM1 and TAT at the C terminus could disrupt the MOR/DOR interaction in the mouse spinal cord, enhance the morphine analgesia, and reduce the antinociceptive tolerance to morphine. Thus, dissociation of MORs from DORs in the cell membrane is a potential strategy to improve opioid analgesic therapies. Highlights ► Activation of δ-opioid receptors (DORs) leads to codegradation of μ-ORs (MORs) ► The first transmembrane domain of MOR (MOR TM1) mediates MOR interaction with DOR ► Plasma membrane-inserted TAT-fused MOR TM1 dissociates MORs from DORs in vivo ► Disruption of the DOR/MOR interaction in C-afferents reduces morphine tolerance
language: eng
source:
identifier: ISSN: 0896-6273 ; DOI: 10.1016/j.neuron.2010.12.001
fulltext: fulltext
issn:
  • 08966273
  • 0896-6273
url: Link


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titleFacilitation of μ-Opioid Receptor Activity by Preventing δ-Opioid Receptor-Mediated Codegradation
creatorHe, Shao-Qiu ; Zhang, Zhen-Ning ; Guan, Ji-Song ; Liu, Hong-Rui ; Zhao, Bo ; Wang, Hai-Bo ; Li, Qian ; Yang, Hong ; Luo, Jie ; Li, Zi-Yan ; Wang, Qiong ; Lu, Ying-Jin ; Bao, Lan ; Zhang, Xu
ispartofNeuron, 2011, Vol.69(1), pp.120-131
identifierISSN: 0896-6273 ; DOI: 10.1016/j.neuron.2010.12.001
descriptionδ-opioid receptors (DORs) form heteromers with μ-opioid receptors (MORs) and negatively regulate MOR-mediated spinal analgesia. However, the underlying mechanism remains largely unclear. The present study shows that the activity of MORs can be enhanced by preventing MORs from DOR-mediated codegradation. Treatment with DOR-specific agonists led to endocytosis of both DORs and MORs. These receptors were further processed for ubiquitination and lysosomal degradation, resulting in a reduction of surface MORs. Such effects were attenuated by treatment with an interfering peptide containing the first transmembrane domain of MOR (MOR TM1), which interacted with DORs and disrupted the MOR/DOR interaction. Furthermore, the systemically applied fusion protein consisting of MOR TM1 and TAT at the C terminus could disrupt the MOR/DOR interaction in the mouse spinal cord, enhance the morphine analgesia, and reduce the antinociceptive tolerance to morphine. Thus, dissociation of MORs from DORs in the cell membrane is a potential strategy to improve opioid analgesic therapies. Highlights ► Activation of δ-opioid receptors (DORs) leads to codegradation of μ-ORs (MORs) ► The first transmembrane domain of MOR (MOR TM1) mediates MOR interaction with DOR ► Plasma membrane-inserted TAT-fused MOR TM1 dissociates MORs from DORs in vivo ► Disruption of the DOR/MOR interaction in C-afferents reduces morphine tolerance
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subjectMorphine ; Opioid Receptors (Type Delta) ; Spinal Cord ; Pain Perception ; Drug Tolerance ; Transmembrane Domains ; Endocytosis ; Ubiquitination ; Analgesia ; Cell Membranes ; Opioid Receptors (Type Mu) ; Opioids ; Analgesics ; Fusion Protein ; Lysosomes ; Neurobiology;
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titleFacilitation of μ-Opioid Receptor Activity by Preventing δ-Opioid Receptor-Mediated Codegradation
descriptionδ-opioid receptors (DORs) form heteromers with μ-opioid receptors (MORs) and negatively regulate MOR-mediated spinal analgesia. However, the underlying mechanism remains largely unclear. The present study shows that the activity of MORs can be enhanced by preventing MORs from DOR-mediated codegradation. Treatment with DOR-specific agonists led to endocytosis of both DORs and MORs. These receptors were further processed for ubiquitination and lysosomal degradation, resulting in a reduction of surface MORs. Such effects were attenuated by treatment with an interfering peptide containing the first transmembrane domain of MOR (MOR TM1), which interacted with DORs and disrupted the MOR/DOR interaction. Furthermore, the systemically applied fusion protein consisting of MOR TM1 and TAT at the C terminus could disrupt the MOR/DOR interaction in the mouse spinal cord, enhance the morphine analgesia, and reduce the antinociceptive tolerance to morphine. Thus, dissociation of MORs from DORs in the cell membrane is a potential strategy to improve opioid analgesic therapies. Highlights ► Activation of δ-opioid receptors (DORs) leads to codegradation of μ-ORs (MORs) ► The first transmembrane domain of MOR (MOR TM1) mediates MOR interaction with DOR ► Plasma membrane-inserted TAT-fused MOR TM1 dissociates MORs from DORs in vivo ► Disruption of the DOR/MOR interaction in C-afferents reduces morphine tolerance
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titleFacilitation of μ-Opioid Receptor Activity by Preventing δ-Opioid Receptor-Mediated Codegradation
authorHe, Shao-Qiu ; Zhang, Zhen-Ning ; Guan, Ji-Song ; Liu, Hong-Rui ; Zhao, Bo ; Wang, Hai-Bo ; Li, Qian ; Yang, Hong ; Luo, Jie ; Li, Zi-Yan ; Wang, Qiong ; Lu, Ying-Jin ; Bao, Lan ; Zhang, Xu
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abstractδ-opioid receptors (DORs) form heteromers with μ-opioid receptors (MORs) and negatively regulate MOR-mediated spinal analgesia. However, the underlying mechanism remains largely unclear. The present study shows that the activity of MORs can be enhanced by preventing MORs from DOR-mediated codegradation. Treatment with DOR-specific agonists led to endocytosis of both DORs and MORs. These receptors were further processed for ubiquitination and lysosomal degradation, resulting in a reduction of surface MORs. Such effects were attenuated by treatment with an interfering peptide containing the first transmembrane domain of MOR (MOR TM1), which interacted with DORs and disrupted the MOR/DOR interaction. Furthermore, the systemically applied fusion protein consisting of MOR TM1 and TAT at the C terminus could disrupt the MOR/DOR interaction in the mouse spinal cord, enhance the morphine analgesia, and reduce the antinociceptive tolerance to morphine. Thus, dissociation of MORs from DORs in the cell membrane is a potential strategy to improve opioid analgesic therapies. Highlights ► Activation of δ-opioid receptors (DORs) leads to codegradation of μ-ORs (MORs) ► The first transmembrane domain of MOR (MOR TM1) mediates MOR interaction with DOR ► Plasma membrane-inserted TAT-fused MOR TM1 dissociates MORs from DORs in vivo ► Disruption of the DOR/MOR interaction in C-afferents reduces morphine tolerance
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