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

Shao Qiu He, Zhen Ning Zhang, Ji Song Guan, Hong Rui Liu, Bo Zhao, Hai Bo Wang, Qian Li, Hong Yang, Jie Luo, Zi Yan Li, Qiong Wang, Ying Jin Lu, Lan Bao, Xu Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

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 (MORTM1), which interacted with DORs and disrupted the MOR/DOR interaction. Furthermore, the systemically applied fusion protein consisting of MORTM1 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.

Original languageEnglish (US)
Pages (from-to)120-131
Number of pages12
JournalNeuron
Volume69
Issue number1
DOIs
StatePublished - Jan 13 2011
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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