Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Elsevier Science full text link Elsevier Science Free PMC article
Full text links

Actions

Share

Review
.2016 Jul;68(3):631-700.
doi: 10.1124/pr.114.008979.

Molecular Pharmacology of δ-Opioid Receptors

Affiliations
Review

Molecular Pharmacology of δ-Opioid Receptors

Louis Gendron et al. Pharmacol Rev.2016 Jul.

Abstract

Opioids are among the most effective analgesics available and are the first choice in the treatment of acute severe pain. However, partial efficacy, a tendency to produce tolerance, and a host of ill-tolerated side effects make clinically available opioids less effective in the management of chronic pain syndromes. Given that most therapeutic opioids produce their actions via µ-opioid receptors (MOPrs), other targets are constantly being explored, among which δ-opioid receptors (DOPrs) are being increasingly considered as promising alternatives. This review addresses DOPrs from the perspective of cellular and molecular determinants of their pharmacological diversity. Thus, DOPr ligands are examined in terms of structural and functional variety, DOPrs' capacity to engage a multiplicity of canonical and noncanonical G protein-dependent responses is surveyed, and evidence supporting ligand-specific signaling and regulation is analyzed. Pharmacological DOPr subtypes are examined in light of the ability of DOPr to organize into multimeric arrays and to adopt multiple active conformations as well as differences in ligand kinetics. Current knowledge on DOPr targeting to the membrane is examined as a means of understanding how these receptors are especially active in chronic pain management. Insight into cellular and molecular mechanisms of pharmacological diversity should guide the rational design of more effective, longer-lasting, and better-tolerated opioid analgesics for chronic pain management.

Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Organization of theOprd gene and its regulatory elements. In all species, the DOPr gene (Oprd) occupies approximately 32 kb on the chromosome. The upper panel illustrates the coding region interrupted by two introns (26 kb and 3 kb) located after TM domains 1 and 4. Regulatory elements and transcription factors are illustrated in the lower panel. Note that most of these findings have been described upon studying the mouseOprd. Numbers above the map correspond to the 5′ ends of the transcription factor binding sites (blue circles) in relation to the initiation codon (designated by +1). Ets, E twenty-six; Ik, Ikaros; NF-κB, nuclear factorκB; Sp1, specificity protein 1; Sp3, specificity protein 3; TF, transcription factor; USF, upstream stimulatory factor; UTR, untranslated region. This figure is adapted from Wei and Loh (2011).
Fig. 2.
Fig. 2.
Primary and secondary amino acid structures of the DOPr and its conserved motifs. (A) The human DOPr in the serpentine format is shown. In all species, the DOPr contains 372 amino acid residues arranged into 7 TM-spanning domains. Motifs that are highly conserved within the rhodopsin-like GPCRs appear in gray, putative phosphorylation sites are in green, and consensusN-glycosylation sites are in red. Theβarr binding sites are also shown. (B) The primary amino acid sequence alignment reveals a >90% homology of mouse, rat, and human DOPrs. The amino acid sequences forming the putative TMHs are highlighted in yellow. The most common human polymorphism (Phe27/Cys27) is highlighted in light blue.
Fig. 3.
Fig. 3.
DOPr-NTI crystal structure. The DOPr structure is shown in blue and residues around the allosteric sodium site appear as green sticks. Sodium is shown as a blue sphere; waters in the first and second coordination shells are shown as red and magenta spheres, respectively. NTI is shown as orange sticks. This figure is adapted from Fig. 1A in Fenalti et al. (2014), generated by using coordinates deposited in the Protein Data Bank under accession code 4NH6.
Fig. 4.
Fig. 4.
DOPr structure (green) bound to DIPP-NH2 (blue sticks) superimposed on a DOPr structure (orange) bound to NTI (magenta sticks). This figure is adapted from Fig. 2D in Fenalti et al. (2015), generated by using coordinates deposited in the Protein Data Bank under accession code 4RWD.
Fig. 5.
Fig. 5.
Naturally occurring peptide DOPr agonists.
Fig. 6.
Fig. 6.
Peptide DOPr agonists.
Fig. 7.
Fig. 7.
Nonpeptide DOPr agonists.
Fig. 8.
Fig. 8.
Peptide DOPr antagonists.
Fig. 9.
Fig. 9.
Nonpeptide DOPr antagonists.
Fig. 10.
Fig. 10.
Peptide MOPr agonists/DOPr antagonists.
Fig. 11.
Fig. 11.
Nonpeptide MOPr agonists/DOPr antagonists.
Fig. 12.
Fig. 12.
Trafficking of DOPr. Two pathways have been proposed: regulated (secretory) and constitutive. (A) DOPrs are synthesized in ribosomes within the ER. (B) A large majority of DOPrs are targeted to lysosomes for degradation. (C) Only successfully folded proteins reach the Golgi apparatus, where they mature and undergo glycosylation. (D and E) Mature DOPrs are trafficked to the plasma membrane via either a constitutive pathway involving cytoskeletal proteins (including cofilin andβarr-1) (D) and/or a regulated (secretory) pathway (E). See Table 2 for a summary of evidence.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. (1991) Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J Pharmacol Exp Ther 258:299–303. - PubMed
    1. Abu-Helo A, Simonin F. (2010) Identification and biological significance of G protein-coupled receptor associated sorting proteins (GASPs). Pharmacol Ther 126:244–250. - PubMed
    1. Acosta CG, López HS. (1999) delta opioid receptor modulation of several voltage-dependent Ca(2+) currents in rat sensory neurons. J Neurosci 19:8337–8348. - PMC - PubMed
    1. Ahuja S, Smith SO. (2009) Multiple switches in G protein-coupled receptor activation. Trends Pharmacol Sci 30:494–502. - PubMed
    1. Allouche S, Hasbi A, Ferey V, Sola B, Jauzac P, Polastron J. (2000) Pharmacological delta1- and delta2-opioid receptor subtypes in the human neuroblastoma cell line SK-N-BE: no evidence for distinct molecular entities. Biochem Pharmacol 59:915–925. - PubMed

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full text links
Elsevier Science full text link Elsevier Science Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp