title: Facilitation of μ-opioid receptor activity by preventing δ-opioid receptor-mediated codegradation.
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 (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.
authors.affiliation: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
authors.forename: Shao-Qiu
authors.initials: SQ
authors.lastname: He
authors.forename: Zhen-Ning
authors.initials: ZN
authors.lastname: Zhang
authors.forename: Ji-Song
authors.initials: JS
authors.lastname: Guan
authors.forename: Hong-Rui
authors.initials: HR
authors.lastname: Liu
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.forename: Hai-Bo
authors.initials: HB
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.forename: Zi-Yan
authors.initials: ZY
authors.lastname: Li
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.forename: Ying-Jin
authors.initials: YJ
authors.lastname: Lu
authors.forename: Lan
authors.initials: L
authors.lastname: Bao
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000698:Analgesia / Q000379:methods; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement / Q000379:methods; D010455:Peptides / Q000494:pharmacology; D010957:Plasmids; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination
chemical_list: D000701:Analgesics, Opioid; D010455:Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009020:Morphine