Agonist-specific down-regulation of the human δ-opioid receptor

Takashi Okura, Eva V. Varga, Yoshiaki Hosohata, Edita Navratilova, Scott M. Cowell, Kenner Rice, Hiroshi Nagase, Victor J. Hruby, William R. Roeske, Henry I. Yamamura

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20 Scopus citations


Down-regulation of the δ-opioid receptor contributes to the development of tolerance to δ-opioid receptor agonists. The involvement of the carboxy terminus of the mouse δ-opioid receptor in peptide agonist-mediated down-regulation has been established. In the present study, we examined the down-regulation of the truncated human δ-opioid receptor by structurally distinct δ-opioid receptor agonists. Chinese hamster ovary (CHO) cells, expressing the full-length or truncated epitope-tagged human δ-opioid receptors were incubated with various δ-opioid receptor agonists (100 nM, 24 h), and membrane receptor levels were determined by [3H]naltrindole saturation binding. Each δ-opioid receptor agonist tested down-regulated the full-length receptor. Truncation of the carboxy terminus abolished down-regulation by all δ-opioid receptor agonists, except SNC80 ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- methoxybenzyl]N,N-diethylbenzamide). In addition, truncation of the C-terminus completely attenuated [D-Pen2-D-Pen5]enkephalin (DPDPE), but not SNC80-mediated [32P] incorporation into the protein immunoreactive with an anti-epitope-tagged antibody. These findings suggest that SNC80-mediated phosphorylation and down-regulation of the human δ-opioid receptor involves other receptor domains in addition to the carboxy terminus. Pertussis toxin treatment did not block SNC80-mediated down-regulation of the truncated Et-hDOR, indicating that the down-regulation is independent of Gi/o protein activation and subsequent downstream signaling.

Original languageEnglish (US)
Pages (from-to)9-16
Number of pages8
JournalEuropean Journal of Pharmacology
Issue number1
StatePublished - Jan 10 2003


  • Agonist-directed trafficking
  • Down-regulation
  • Human
  • Pertussis toxin
  • Phosphorylation
  • δ-Opioid receptor

ASJC Scopus subject areas

  • Pharmacology


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